Liquids rich in noble gas and methods of their preparation and use

ABSTRACT

Provided herein is a novel composition for oral administration and delivery of Noble gas, such as xenon or argon. Methods of treating and preventing neuronal or cardiovascular damage with such compositions are also provided. The present invention relates generally to the fields of molecular biology, medicine and nutraceuticals. More particularly, it concerns methods for oral delivery of inert gas compositions, such as Xenon or Argon, for the treatment and prevention of disease.

This application claims the benefit of U.S. Provisional PatentApplication Nos. 61/788,808, filed Mar. 15, 2013, and 61/889,901, filedOct. 11, 2013, both of which are incorporated herein by reference intheir entirety.

The invention was made with government support under Grant Nos.NS067454, HL074002, and HL059586 awarded by the National Institutes ofHealth. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to the fields of molecularbiology, medicine and nutraceuticals. More particularly, it concernsmethods for oral delivery of inert gas compositions, such as Xenon orArgon, for the treatment and prevention of disease.

2. Description of Related Art

Both Xenon (Xe) and Argon (Ar) are, pleiotypic cytoprotective gases,which have unique advantages that include rapid diffusion acrossbiological barriers such as the blood-brain barrier (BBB) and completepassage across cell membranes due to its low blood-gas partitioncoefficient. In animal models, Xe given as a continuous gas inhalationhas demonstrated potent neuroprotective and myocardical protectiveeffects. Xe protects against oxygen and glucose deprivation (OGD) andprotects against hypoxia/ischemia by alteration of molecules involved inneuronal ischemic tolerance. Xe helps to induce transcription of severalpro-survival genes including brain-derived neurotrophic factor (BDNF)and pro-survival proteins such as Bcl₂ which promote cell tolerance toischemic injury. Xe interacts with the human immune system by modulatinginflammatory cytokines such as TNF-α and IL-6 in monocytes. Xe helps tosustain release of hypoxia inducible factor 1 alpha (HIF-1α) and otherproteins. All these pathways are implicated in organ protection.

Current methods for gas delivery involve inhalation and administrationof a gas donor. However, Xe or Ar inhalation cannot be practically givenin many situations as the required high Xe or Ar concentration forinhalation limits the fraction of inspired oxygen necessary for cellsurvival. In addition, there is the difficulty of developing acontinuous inhalation strategy for patients as daily use. Improvedmethods of delivery of Xe or Ar are greatly needed.

SUMMARY OF THE INVENTION

Embodiments of the present invention relates generally to treatmentmethods, pharmaceuticals and nutraceuticals (a portmanteau of the words“nutrition” and “pharmaceutical”, which is a food or food product withhealth and medical benefits, including the prevention and treatment ofdisease). More particularly, it concerns methods for primarily oraldelivery of inert gas compositions to the gastrointestinal tract (GI),comprising a Noble gas such as Helium, Neon, Argon, Krypton and/orXenon. Such gases can be delivered as part of a method for theprevention and/or treatment of diseases in the heart and brain,including but not limited to atherosclerosis-associated ischemic heartdisease, stroke and other neuron degenerative condition, such asdementia (e.g., Alzheimer disease). In certain aspects, compositionscomprising Noble gases provide reduction in one or more marker ofinflammation or general improvement in well-being.

In a first embodiment there is provided a liquid (or semi-liquid, e.g.,pastes or gels) formulation having an enhanced concentration ofencapsulated Noble gas (e.g., the gas may be encapsulated to achieve aspecified concentration). The Noble gas can be selected from Helium,Neon, Argon, Krypton, Xenon or a mixture thereof. As used herein theencapsulated Noble gas can be provided as a gas dissolved in a lipid andemulsified, encapsulated in a liposome formulation and/or encapsulatedin a water soluble molecule (e.g., cyclodextrin). In general theencapsulation allows the composition to achieve a higher gas contentthan can be achieved in an equal amount of water (absent suchencapsulation) and the same temperature and pressure. In preferredaspects, the composition is formulated for oral delivery

In a certain embodiments there is provided a nutraceutical (such as abeverage) composition comprising a substantially aqueous component and adissolved Noble gas, wherein a portion of the Noble gas in encapsulatedto enhance aqueous solubility. In some aspects, the encapsulated Noblegas may be encapsulated in a lipid, such as in a liposome or in a lipidphase that is emulsified in the composition. In still further aspects,the Noble gas (e.g., Xe Ar, Kr, Ne or He) is encapsulated in awater-soluble molecule, such as a water soluble polymer. In stillfurther aspects, the Noble gas is encapsulated in α-, β-, orγ-cyclodextrin or a mixture thereof. Further molecules that may be usedfor Noble gas encapsulation are detailed below.

In yet a further embodiment the invention provides single servingnutraceutical composition including but not limited to beverages, gels,pastes, tablets, and capsules. For example, the composition may compriseabout 1, 2, 3, 4, 5 or 10 to about 15, 20, 25, 30, 35, 40, 45 or 50 mlof the composition. In further aspects, the composition may compriseabout 10, 15, 25, 30, 35, 40, 45 or 50 to about 100, 150, 200, 250, 300,350, 400, 450 or 500 ml of a composition (e.g., a substantially aqueouscomposition). In some aspects, a composition of the embodimentscomprises 0.01 to 15 g or about 0.1 to 200 mg of dissolved Noble gas (ora mixture of two or more such gases), wherein a portion of the Noble gasis encapsulated to enhance aqueous solubility. As detailed above theNoble gas may be encapsulated or solubilized in a (emulsified) lipidcomponent, in a liposome or in a water-soluble molecule. For example, insome aspects, the Noble gas (e.g., Xe) is encapsulated in awater-soluble polymer, such as cyclodextrin. In certain aspects, theamount of dissolved Noble gas (e.g., Xe) in the formulation is about 0.1mg to 10 g, 0.1 to 1,000 mg, 0.1 to 500 mg, 0.5 to 100 mg, 1 to 100 mg,1 to 50 mg, 1 to 25 mg or 1 to 10 mg. Likewise, the volume of liquidcomponent in the formulation can be adjusted to provide an optimalamount of the Noble gas in a single serving. For example, the singleserving beverage may comprise a total volume of between about 1 to 10ml, 10 to 25 ml, 25 to 50 ml, 50 to 500 ml, 50 to 300 ml, 100 to 300 mlor 200 to 400 ml. As detailed further herein, in certain preferredembodiments, such a single serving nutraceutical is provided in agas-impermeable sealed container, such as a bottle, can or foil orpolymer package. Likewise, in some aspects, a package of single-servingnutraceutical beverages is provided comprising 4, 6, 8, 12, 24 or moresingle serving compositions such as beverages, each comprised in aseparate sealed container.

As detailed supra, certain aspects of the embodiments concerncompositions comprising Noble gases (e.g., Xe), at least a portion ofwhich is encapsulated in cyclodextrin (CD) (e.g., β-cyclodextrin). Insome cases, cyclodextrin for use according to the embodiments willinclude hydrophilic groups that further enhance the aqueous solubility.For example, in certain aspects, the CD is a hydroxypropyl-CD, such ashydroxypropyl-beta-cyclodextrin. A composition may comprise, forinstance, about 0.01 to about 5.0 mg/ml; about 0.05 to about 2.0 mg/ml;about 0.1 to about 1.5 mg/ml or about 0.1 to about 1.0 mg/ml of a CD. Insome specific aspects, the composition comprises 0.1 to about 1.0 mg/mlof hydroxypropyl β-CD. In still further aspects, a composition comprisesabout 0.1 to about 5.0 ml; about 0.1 to about 4.0; about 0.1 to about3.8; about 0.1 to about 2.0; about 0.1 to about 1.0 ml; or 0.5 to about1.0 ml of Noble gas (e.g., Xe) per 0.5 mg of cyclodextrin in thecomposition (e.g., at standard temperature-pressure). In particular, acomposition may comprise about 0.1 to about 5.0 ml; about 0.1 to about4.0; about 0.1 to about 3.8; about 0.1 to about 2.0; about 0.1 to about1.0 ml; or 0.5 to about 1.0 ml of Xe per 0.5 mg of β-cyclodextrin (e.g.,hydroxypropyl β-CD). In a very specific aspect, a composition comprisesup to about 3.8 ml of Xe to 0.5 mg of a CD molecule (e.g., per ml ofwater).

Additional cyclodextrin molecules that can be used according to theembodiments (in either oil or water compositions depending on thedesired solubility include, without limitation, methyl-β-cyclodextrin,randomly methylated-β-cyclodextrin, dimethyl-β-cyclodextrin, randomlydimethylated-β-cyclodextrin, trimethyl-β-cyclodextrin, acetylateddimethyl-β-cyclodextrin, 2-Hydroxyethyl-β-cyclodextrin,2-Hydroxypropyl-β-cyclodextrin, 3-Hydroxypropyl-β-cyclodextrin,hydroxybutenyl-β-cyclodextrin, 2,3-Dihydroxypropyl-β-cyclodextrin,2-Hydroxypropyl-γ-cyclodextrin, glucosyl-β-cyclodextrin,maltosyl-β-cyclodextrin, glucuronyl-glucosyl-β-cyclodextrin, alkylatedβ-cyclodextrin, 2,6-Di-O-ethyl-β-cyclodextrin,2,3,6-Tri-O-ethyl-β-cyclodextrin, acylated β-Cyclodextrin,2,3,6-Tri-O-acyl(C2-C18)-β-cyclodextrin,2,3,6-Tri-O-butanoyl-β-cyclodextrin, 2,3,6-Tri-O-valeryl-β-cyclodextrin,2,3,6-Tri-O-octyl-β-cyclodextrin,O-Carboxymethyl-O-ethyl-β-cyclodextrin, β-Cyclodextrin sulfate,sulfobutyl ether group-β-cyclodextrin, or sulfobutyl ethergroup-β-cyclodextrin.

The methodologies demonstrated herein can provide very highconcentrations of Noble gas in a liquid format. However, in some cases,liquids or semi-liquids (including e.g., a beverage) of the embodimentsmay comprise a relatively moderate amount of a Noble gas such as Xe. Forexample, such a beverage may comprise a dissolved Xe concentration (whenin a sealed container) of about 1.0 to about 5,000 μg/ml, about 10 toabout 1,000 μg/ml, about 100 to about 800 μg/ml, about 1.0 to about 100μg/ml, 5.0 to about 50 μg/ml, about 10 to about 100 μg/ml or about 10 toabout 50 μg/ml. For example, Xe dissolved in water at standardtemperature and pressure can have a concentration of about 600 μg/ml. Ina further aspect, a beverage is provided having a high concentration ofXe, such as about 1 mg/ml to about 100 mg/ml, 1 mg/ml to about 50 mg/ml,about 1 mg/ml to about 30 mg/ml, or about 10 mg/ml to about 50 mg/ml. Insome aspects, a beverage is provided comprising a Xe level of about 10mg/ml to about 15, 20, 25, 30, 35, 40, 45 or 50 mg/ml Xe (e.g., such asa beverage comprising pressurized and/or encapsulated Xe). For example,a formulation comprising cyclodextrin (hydroxypropyl β-CD) encapsulatedXe can have a Xe concentration of about 22.4 mg/ml when formulated at 3atm and 4° C., then brought to standard ambient temperature and pressure(SATP)).

In some aspects, the methodologies and compositions herein concern Argongas provided in a liquid or semi-liquid format (e.g., as a beverage).For example, such a composition may comprise a dissolved Arconcentration (when in a sealed container) of about 1.0 to about 1,000μg/ml, about 10 to about 500 μg/ml, about 20 to about 500 μg/ml, about30 to about 250 μg/ml, about 40 to about 200 μg/ml, about 50 to about100 μg/ml or about 40 to about 75 μg/ml. For example, Ar dissolved inwater at standard temperature and pressure can have a concentration ofabout 55 μg/ml. In a further aspect, a beverage is provided having ahigh concentration of Ar (such as Ar encapsulated in a polymer or anoil), such as about 0.01 μg/ml to about 1 mg/ml, 0.1 μg/ml to about 1mg/ml, about 1 μg/ml to about 500 μg/ml, about 10 μg/ml to about 500μg/ml, about 100 μg/ml to about 500 μg/ml, or about 200 μg/ml to about500 μg/ml. For example, a formulation comprising an oil encapsulated Arat SATP may have an Ar concentration of about 165 μg/ml.

In still yet a further aspect, a composition of the embodiments ischaracterized in having a Noble gas content (at standard ambienttemperature and pressure; SATP) of at least about 0.5 mM, 0.6 mM, 0.7mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6mM, 1.7 mM, 1.8 mM, 1.9 mM or 2.0 mM. In some aspects, the Noble gas isin a concentration of at least 4.5, 4.6., 4.7, 4.8, 4.9 or 5.0 mM. Thus,in some aspects, the composition comprises a Noble gas content ofbetween about 5.0 and 50 mM, 5.0 and 25 mM, 5.0 and 20.0 mM, 5.0 and 15mM or 5.0 and 10 mM at SATP. In still further aspects, the compositioncomprises a Xenon content of greater than about 5.0 mM, such as betweenabout 5.0 and 50 mM, 5.0 and 25 mM, 5.0 and 20.0 mM, 5.0 and 15 mM or5.0 and 10 mM at SATP. In still further aspects, a composition comprisesAr at a concentration of greater than 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM,0.9 mM, 1.0 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM,1.8 mM, 1.9 mM or 2.0 mM. For example, the composition may comprisebetween about 1.0 and 10 mM, 1.5 and 10 mM, 1.5 and 10 mM, 2.0 and 10 mMor 2.0 and 5 mM Ar at SATP.

In still further aspects, a composition of the embodiments is defined bythe Noble gas content as compared to the aqueous component (e.g., water)content. For example, a composition may comprise a Noble gas to aqueouscomponent ratio of between about 1:20 and 4:1; about 1:10 and 4:1; about1:9 and 4:1; about 1:2 and 4:1; 1:1 and 4:1; about 1.5:1 and 4:1; about1:20 and 1:1; about 1:10 and 1:1; or about 2:1 and 3:1 (volume:volume).In some aspects, the Noble gas to aqueous component ratio is greaterthan 1:10; 1:9; or 1:5. In certain aspects, the Noble gas to aqueouscomponent ratio is greater than 1:1 or greater than 2:1. Thus, in somespecific aspects, a composition comprises a Xe to water ratio of betweenabout 1:2 and 4:1; 1:1 and 4:1 or 1.5:1 and 4:1 or 2:1 and 3:1(volume:volume), such as a ratio greater than about 2:1.

In certain embodiments compositions such as a beverage composition ofthe embodiments further comprise additional components such aspreservatives, flavoring agents, dyes, vitamins, anti-oxidants, plant ormicrobial extracts, salts (electrolytes, glycerol, sodium, potassium andchloride), alcohols, lipids, oils, or a mixture thereof. Thus, in someaspects, a beverage or other form of the embodiments is further definedas an herbal, vitamin or energy-providing nutraceutical composition.

In a further embodiment the invention provides, a pharmaceutical ornutraceutical composition comprising lipids such as an edible oilcomponent comprising a soluble gas, such as Noble gas (e.g., xenon orargon gas). Examples, of oils for such a composition include, withoutlimitation, flaxseed oil, rapeseed oil, soybean oil, walnut oil, fishoil, safflower oil, sunflower oil, corn oil, cotton seed oil, peanutoil, palm oil or olive oil. In one aspect, the oil may comprisepolyunsaturated fatty acids (PUFA), such as an oil comprising at least5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more PUFAs. In stillfurther aspects, the oil comprises omega-3 fatty acids, which may aid inbiological uptake of the gases of the embodiments. In still furtheraspects, the oil component is saturated or super saturated with xenon orargon gas.

In a further embodiment, an oil-gas composition may be further comprisedin an emulsion. For example, an emulsion can comprise (a) 25% to 50%,60%, 70%, 80%, 90%, 95% or more by volume oil, (the oil comprisingsoluble xenon or argon gas) and (b) 1%, 2%, 3%, 5%, 10%, 20%, or 30% toabout 75% or 85% by volume aqueous solution. In some aspects, theaqueous solution comprises water (e.g., spring water), fruit juice,vegetable juice or other nutritious beverage. In some aspects, thecomposition may further comprise phospholipid, detergent, or proteincomponents. In some aspects, the composition further comprisesphospholipids, detergents, flavorings, dyes, emulsifiers, co-emulsifiersand/or protein components. For example, the detergent can be a plantsurfactant, a synthetic detergent or a bile acid. In certain aspects,the detergent is lithocholic acid, deoxycholic acid, taurocholic acid,glycocholic acid, chenodeoxycholic acid, or cholic acid. Examples ofphospholipids for use according to the embodiments include, withoutlimitation, egg phosphocholine (egg PC), soybean PC, DPPC or DOPC.Proteins that may be included are, for example, milk protein, wheyisolate protein, soy protein isolate, potassium caseinate, egg albumin,(Brown) rice protein, hydrolyzed beef protein isolate, pea proteinisolate, hemp protein, or bovine serum albumin.

As detailed above, in certain aspects, oil compositions are providedthat comprise both soluble and insoluble, trapped, or free gases andthat may be in a liquid or semi-liquid form. Gases that may be includedin such compositions include without limitation Noble gases (e.g., He,Ar, Kr, Ne or Xe), CO₂, nitrous oxide, isoflurane and servoflurane. Inpreferred embodiments, a lipid oil composition comprises soluble xenonor argon gas (and, in some cases, also comprise insoluble or free Xe orAr or other Noble gas). In some aspects, a composition comprises lowoxygen or nitrogen content, or is essentially free of these gases. Insome aspects, the oil composition is semi-saturated or saturated with agas. In still further aspects, a lipid oil can be supersaturated with agas (e.g., such that the gas is bubbling out of the oil when exposed tothe atmosphere). In some aspects, a lipid oil composition of theembodiments may comprise between about 10 and 500 mg of xenon per ml ofoil (e.g., between about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 mgand about 150, 200, 250, 300, 350, 400, 450 or 500 mg per ml of oil).For example, at SATP an oil may comprise about 0.1 to about 50; about0.1 to about 20 or about 1 to about 15 mg of Xe per ml of oil.

In certain specific aspects, a composition of the embodiments maycomprise (a) 25% to 50% by volume oil (e.g., olive oil or other desiredlipid), (the oil comprising soluble xenon or argon gas); (b) 50% to 75%by volume water solution; (c) 10-30 mg/ml of a phospholipid (e.g., eggphosphocholine); (d) 10-50 mg/ml of a protein (e.g., BSA); and (e) 1-5mg/ml of a detergent (e.g., lithocholic acid). In some aspects, thecomposition may further comprise a preservative, flavoring agent,vitamin, anti-oxidant, or plant extract.

In some aspects, compositions comprising Noble gases may be comprised ina gas impermeable container of any size or shape. In some cases, thecontainer may be pressurized (e.g., pressurized with a Noble gas, suchas xenon or argon gas). In some aspects, such a container may comprise asingle serving or unit dosage of a composition (e.g., in a paste, a gel,a pill, a tablet or capsule). In other cases, a container can comprisemultiple doses (e.g., a multiple dose bottle or a compartmentalizedcontainer). In this later case to may be preferable that the containerbe pressurized and comprise a one-way value to release the compositionwithout exposing the entire content to the atmosphere. In still furtheraspects, such a container may comprise excess gas (e.g., argon or xenon)that maintain the pressure in the vessel when doses of the compositionare released. Such a system is described, for example, in U.S. Pat.Publn. No. 20030177784, which is incorporated herein by reference. Insome cases, the container comprises foil or similar impermeable materialsuch as a polymer, such that the container may be pressured byeffectively dispense liquids or semi-liquids readily.

In a further embodiment, the present disclosure provides a unit dosageof a composition of the embodiments comprised in a gas impermeablecontainer. In certain aspects, the container may be a paste, gel, pill,tablet or a capsule. In another aspect, the container may be a bottle.For example, a container can enclose 1-5 ml; 5-25 ml; 25-100 ml; 125-300ml; 355-500 ml; 500 ml to 1 liter or more of the composition, such as anemulsion of the embodiments.

In some further embodiments there is provided a method of improving thehealth or well-being of a subject comprising administering to thesubject (or providing the subject with) a composition in accordance theembodiments. For example, the subject can be provided with an amount toof a Noble gas composition of the embodiments that is sufficient toreduce the level of at least one marker of inflammation orcardiovascular risk (e.g., blood pressure). For example, in some cases aNoble gas composition is administered in as an oral liquid orsemi-liquid formulation to provide a daily dose equivalent to betweenabout 0.1 to 200 mg/day of Xe. In another example, a daily Xe dose maybe between about 1 to 100 mg, 1 to 50 mg, 1 to 25 mg or 1 to 10 mg perday of Xe. In another example, a Noble gas composition is administeredas an oral formulation to provide a daily dose equivalent to betweenabout 0.1 to 5 g/day of Xe. For instance, the daily dosage of Xe can bebetween about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 and1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 or 5.0 grams per day of Xe. In afurther embodiment, a method comprises administering an oral Xecomposition in a dose of between about 0.1 and 10; 0.1 and 5; 0.5 and 5;1.0 and 3.0; or 2.0 and 3.0 mg (of Xe)/Kg/day. In still further aspects,a method of the embodiment comprises administering (or providing to asubject) a dose of Noble gas (e.g., Xe) to achieve an initial maximalblood concentration of between 10 μM and 500 μM, between 10 μM and 100μM, between 10 μM and 50 μM or an initial maximal blood concentration ofat least 50 or 100 μM. For example, in some aspects, such a dose ofcomposition of the embodiments is administered daily, every two days, orweekly.

In a further embodiment, the present disclosure provides a method ofproviding neurological or cardiovascular protection is a subjectcomprising orally administering an effective amount of a composition inaccordance with any one of the embodiments. In certain aspects, thesubject (e.g., a human subject) has or is at risk for Alzheimer'sdisease, thrombotic stroke, ischemic stroke or cardiac hypertrophy. Insome aspects, the method further comprises administering about 25-300ml/day (70-1,350 mg/day, e.g., 100-1,200 mg/day, 200-1000 mg/day,500-1000 mg/day or 800-1,200 mg/day) to the subject. The composition maybe administered weekly, daily, twice a day, three times a day, every sixhours, every three hours or hourly. Likewise, a composition may beadministered over the period of a week, two weeks, a month or a year. Insome aspects, the method is a method for treating or preventing aneurological disease or neurological injury, such as Alzheimer's diseaseor thrombotic or ischemic stroke. In further aspects, methods areprovided for treating or preventing cardiac hypertrophy, or providingprotection from myocardial ischemia.

In still a further embodiment, the present disclosure provides a methodof reducing beta-amyloid levels in a subject comprising administering aneffective amount of xenon or argon to the subject. In certain aspects,the xenon or argon is administered orally in a composition in accordancewith any one of the embodiments. In still other aspects, the xenon orargon or other Noble gasare administered via inhalation or injection(e.g., comprised liposomes).

In a related embodiment, the present disclosure provides a method oftreating or preventing the progression of Alzheimer's disease in asubject comprising administering an effective amount of xenon or argonor other Noble gas to the subject. In certain aspects, the xenon orargon is administered orally. In other aspects, the xenon or argon orother Noble gas (e.g., He, Ne or Kr) are administered via inhalation orinjection In some aspects, the subject is a subject who is at risk fordeveloping Alzheimer's disease, such as a subject who has or isdiagnosed with a genetic predisposition for Alzheimer's disease.

In yet a further embodiment, the present disclosure provides a method ofmaking a composition for oral administration of xenon or argoncomprising (a) solubilizing xenon or argon gas in an edible oil bymixing the oil and gas to produce an edible oil comprising soluble xenonor argon gas. In some aspects, the method further comprises (b)emulsifying the edible oil comprising the soluble gas in an aqueoussolution (e.g., a solution comprising a detergent or other emulsifier)to produce an emulsion comprising soluble xenon or argon gas. In someaspects, oil and gas are mixed at a pressure of between about 1 atm and6 atm, 2 atm and 6 atm or 2 atm and 4 atm, at a temperature of betweenabout 0° C. and 37° C. or 0° C. and 25° C. In certain aspects,solubilizing xenon or argon gas in an edible oil comprises saturating orsupersaturating the oil with xenon or argon gas. In some aspects, themethod further comprises bottling or capturing the oil or emulsion in agas impermeable container (e.g., a bottle, capsule or pill). Forexample, the container may be pressurized, such as container pressurizedat 2-6 atm. In certain aspects, steps (a)-(b) of the method may beperformed under a xenon or argon or other Noble gas atmosphere (e.g.,He, Ne or Kr).

In yet a further embodiment there is provided a method of making asubstantially aqueous composition comprising a Noble gas comprising: (a)incubating a Noble gas (or a mixture of Noble gases) with a watersoluble encapsulating molecule (e.g., a water soluble polymer); and (b)exposing the encapsulated Noble gas to an aqueous solution to produce anaqueous composition comprising the encapsulated Noble gas. In someaspects, step is (a) is performed at a pressure of between about 2 atmand 10 atm (e.g., a pressure between about 2 atm and 8 atm, 2 atm and 5atm, 2 atm and 4 atm or at a pressure of about 3 atm), at a temperatureof between, e.g., about 25° C. or 4° C. and −180° C. (e.g., for a periodof at least 1, 2, 3, 4 or more hours) to produce an encapsulated Noblegas. In certain aspects the incubating of step (a) is performed at atemperature of between about 0° C. and −150° C., −20° C. and −150° C.,−20° C. and −100° C., −40° C. and −100° C. or at a temperature of about−80° C. and for a period of at least 8 hours, 12 hours, 24 hours, 48hours or for between 8 hours and three days. In some cases, step (b)comprises exposing the encapsulated Noble gas to an aqueous solution ata pressure of between about 2 atm and 10 atm (e.g., a pressure betweenabout 2 atm and 8 atm, 2 atm and 5 atm, 2 atm and 4 atm or at a pressureof about 3 atm), e.g., at a temperature of between about 20° C. and 1°C. For example, step (b) can occur over a period of at least 1, 2, 3, 4or more hours. In still further aspects, the exposing of step (b) isperformed at a pressure of between about 2 atm and 8 atm, 2 atm and 5atm, 2 atm and 4 atm or at a pressure of about 3 atm. In some aspects,the exposing of step (b) is performed at a temperature of between about15° C. and 1° C., 10° C. and 1° C., 8° C. and 2° C., 6° C. and 2° C. orat a temperature of about 4° C. In still further aspects, the exposingof step (b) is for a period of at least 8 hours, 12 hours, 24 hours, 48hours or for between 8 hours and three days. In still further aspects,the exposing of step (b) comprises exposing the encapsulated Noble gasto an aqueous solution that comprises of is a saturated with a Noble gasor a mixture of Noble gases. For example, the solution can be saturatedwith a Noble gas by a method comprising: (i) obtaining a degassedaqueous solution; and (ii) exposing the degassed aqueous solution to aNoble gas at a pressure of between about 2 atm and 10 atm, at atemperature of between about 20° C. and 1° C. for at least 4 hours toproduce an aqueous solution saturated with the Noble gas.

In yet a further embodiment, the present disclosure provides acomposition for use in providing neurological or cardiovascularprotection in a subject, the composition comprising edible oil saturatedwith a Noble gas, such as xenon or argon gas.

In a particular aspect of the embodiments there is provided a method ofdelivery of a Noble in a substantially aqueous composition comprisingsupplying a beer, cider, soda or other carbonated beverage from a tapoperably coupled to a Noble gas canister (e.g., a Xe gas canister), suchthat the Noble gas is used to maintain tap pressure and it therebydissolved into the beverage (e.g., beer) being dispensed from the tap.

As used herein the specification, “a” or “an” may mean one or more. Asused herein in the claim(s), when used in conjunction with the word“comprising”, the words “a” or “an” may mean one or more than one.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and “and/or.” As used herein “another”may mean at least a second or more.

Throughout this application, the term “about” is used to indicate that avalue includes the inherent variation of error for the device, themethod being employed to determine the value, or the variation thatexists among the study subjects.

Other objects, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

FIG. 1. Echocardiographic Measurements to Assess Cardiac Hypotrophy andFunction of C57BL/6J wild type (WT) and apolipoprotein-E (ApoE) knockout(KO) mice in Response to Xe-rich Solution Pre-treatment. FIG. 1A.Intra-ventricular septum in diastole (IVS:d) (mm) FIG. 1B. Leftventricular posterior wall diameter in diastole (LVPW:d) (mm) FIG. 1C.Left ventricular (LV) volume in diastole (LV Vol;d) (μL). *p<0.05, **p<0.01, KO/KO6w compared to WT/WT6w, respectively; # p<0.05, KOcontrol/vehicle compared to KO 6w; §p<0.05, §§p<0.01, §§§p<0.001, KOxenon compared to KO vehicle. WT=Wild type mice; KO=Apo E knockout mice.

FIG. 2. Echocardiographic Measurements on % Ejection fraction (% EF)(FIG. 2A). % Fractional shortening (% FS) (FIG. 2B), and Cardiac output(ml/min)(FIG. 2C). *p<0.05, ** p<0.01, KO/KO6w compared to WT/WT6w,respectively; # p<0.05, KO control/vehicle compared to KO 6w; §p<0.05,§§p<0.01, §§§p<0.001, KO xenon compared to KO vehicle.

FIG. 3. Alterations in Cardiac Mass Morphology in Wild Type (WT) andApo-E Knockout (KO) Mice. FIG. 3A. LV mass corrected (mg). FIG. 3B.Ratio of heart weight (HW) to body weight (BW) (mg/g). WT-6w (n=5): WTmice fed with regular diet for 6^(th) week. KO-6w (n=4): the KO mice fedwith regular diet for 6^(th) week. KO-6w control (n=5): the KO mice fedwith high fat diet and administered by PBS gavage for 6^(th) week. KO-6wvehicle (n=7): the KO fed with high fat diet and vehicles for 6^(th)week. KO-6w Xenon (n=6): the KO fed with high fat diet and administeredwith Xenon-rich-solution for 6^(th) week. *p<0.05, KO/KO6w compared toWT/WT6w, respectively; §p<0.05, KO6w xenon compared to KO6w vehicle.

FIG. 4. Myocardiographic Alterations in Cardiac Function in Wild Typeand Apo-E Knockout Mice in response to Xe-rich Solution Pre-treatment.WT (n=9): wild type mice fed with regular diet at baseline; KO (n=25):Apo E-KO mice fed with regular diet at baseline. WT-6w (n=5): WT micefed with regular diet for 6^(th) week. KO-6w (n=5): the KO mice fed withregular diet for 6^(th) week. KO-6w control (n=4): the KO mice fed withhigh fat diet and administered by PBS gavage for 6^(th) week. KO-6wvehicle (n=7): the KO fed with high fat diet and vehicles for 6^(th)week. KO-6w Xenon (n=6): the KO fed with high fat diet and administeredwith Xenon-rich-solution for 6^(th) week.

FIG. 5. Levels of Brain-derived Neurotrophic Factor (BDNF) in the Heart(FIG. 5A) and Brain (FIG. 5B) in Response to Xe-Rich-SolutionPer-treatment. WT-6w (n=4): WT mice fed with regular diet for 6^(th)week. KO-6w (n=5): the KO mice fed with regular diet for 6^(th) week.KO-6w vehicle (n=7): the KO fed with high fat diet and administered bythe solution gavage at 6^(th) week. KO-6w Xenon (n=6): the KO fed withhigh fat diet and administered by Xenon gavage at 6^(th) week. *p<0.05,** p<0.01, *** p<0.001, KO6w/vehicle/Xenon compared to WT6w,respectively; # p<0.05, KO6w vehicle compared to KO 6w; §p<0.05, KO6wXenon compared to the vehicle.

FIG. 6. Levels of Beta-Amyloid in the Blood (FIG. 6A) and Brain (FIG.6B) in Response to Xe-Rich-Solution Per-treatment. WT-6w (n=5): WT micefed with regular diet for 6^(th) week. KO-6w (n=4): the KO mice fed withregular diet for 6^(th) week. KO-6w control (n=5): the KO mice fed withhigh fat diet and administered by PBS gavage for 6th week. KO-6w vehicle(n=7): the KO fed with high fat diet and vehicles for 6^(th) week. KO-6wXenon (n=6): the KO fed with high fat diet and administered byXenon-rich-solution for 6^(th) week. *p<0.05, KO6w vehicle compared toWT6w; §§p<0.01, KO6w Xenon compared to the vehicle.

FIG. 7. Xenon-rich-Solution to Increase Brain Tolerance to IschemicInjury. FIG. 7A. Infarct size. FIG. 7B. Percent infarct volume. FIG. 7C.Limb placement. FIG. 7D. Grid walking.

FIG. 8. Example of the exemplary mouse experimental protocol.

FIG. 9. Example of the rat experimental protocol.

FIG. 10. Initial Xenon caging experiments. (A) A schematic showing thestructure of CD used for caging of Xe. (B) A schematic showing thephysical properties of α-, β- and γ-CD as compared to a Xe atom. (C)Graph shows the results of studies to determine the effects of pressureon Xe encapsulation in CD. (D) Graph shows the effects of temperature onthe on Xe encapsulation in CD.

FIG. 11. Upper panel shows an exemplary protocol for production of Xeenhanced water using CD caging. Lower panel is a graph showing thevolume of dissolved Xe per 5 ml water that was achieved using theindicated methods.

FIG. 12. Echocardiographic Measurements of Mice Treated with Xe Water.Graphs show the results of echocardiographic measurement of (1) WT micefed with regular diet for 6th week (WT-6w, n=5); (2) Apo E knockout micefed with high fat diet and normal water control (KO6w control, n=13);(3) vehicle control mice feed with water containing cyclodextrin only(KO6w vehicle, n=5); or (4) Apo E knockout mice fed with Xe-rich-water(KO6w Xenon, n=5) after 6 weeks of treatment. Graphs show the results ofmeasurements of intra-ventricular septum (IVS) volume, percent leftventricular (LV) ejection fraction (EF), left ventricular posterior wallthickness (LVPW), percent LV fractional shortening (FS), LV volume andcardiac output (CO).

FIG. 13. Effects of Xe on ischemic stress. Graph in the left panels showthe results of studies to measure CKMB Creatine Kinase (CKMB) levels inthe control mice versus Xe-treated animals. Graph in the right panelshows the results of studies to measure troponin expression levels inthe control mice versus Xe-treated animals (Mean±SE, n=5, ^(§)p<0.01).

FIG. 14. Xe-rich-water decreases expression of β-amyloid in brain andblood. Graphs show the amount of β-amyloid that was found plasma (leftpanel) or brain (right panel) after 6 weeks of treatment. WT6w (n=10)indicates mice fed with regular diet at 6th week; KO-6w (n=5) indicatesApoE knock mice fed with regular diet at 6th week; KO-6w vehicle (n=7)indicates ApoE knock mice fed with high fat diet and water containingcyclodextrin at 6th week; KO-6w Xenon (n=6) indicates ApoE knock micefed with high fat diet and Xe-rich-Water at 6th week. *p<0.05, KO6wvehicle compared to WT6w; §§p<0.01, KO6w Xenon compared to the vehicle.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Nobel gases such as Xenon (Xe) and Argon (Ar) are attractive since theymay improve health and well-being at low dosages and are also potentialtherapeutics if given at higher dosages. However, there are a wide rangeof difficulties in attempting to administer such gases to humans. Inparticular, the amount of gas that can be administered via inhalation isa very serious limitation. Likewise, because these gases are chemicallyneutral and non-polar formulation into other delivery vehicles hasproved to a very difficult challenge.

Disclosed herein are solutions rich in a Noble gas, such as Xe or Ar fororal delivery to humans and in some cases other animals of interest. Insome aspects, these solutions use lipids including but not limited tooils such as edible oils (e.g., omega-3 rich oils) from known foods as acarrier media to provide increased solubility of such Noble gases.Alternatively or additionally aqueous solutions can incorporate a Noblegas encapsulated in polymer (e.g., cyclodextrin includes:α-cyclodextrin: 6-membered sugar ring molecule, β-cyclodextrin:7-membered sugar ring molecule, and γ-cyclodextrin: 8-membered sugarring molecule and various derivatives). Derivatives of cyclodextrinsinclude but are not limited to Methyl-β-cyclodextrin, randomlymethylated-β-cyclodextrin, dimethyl-β-cyclodextrin, randomlydimethylated-β-cyclodextrin, Trimethyl-α-cyclodextrin; Acetylateddimethyl-β-cyclodextrin: 2-Hydroxyethyl-β-cyclodextrin,2-Hydroxypropyl-β-cyclodextrin, 3-Hydroxypropyl-β-cyclodextrin;Hydroxybutenyl-β-cyclodextrin: 2,3-Dihydroxypropyl-β-cyclodextrin,2-Hydroxypropyl-γ-cyclodextrin; glucosyl-β-cyclodextrin;maltosyl-β-cyclodextrin; glucuronyl-glucosyl-β-cyclodextrin; 2,hydrophobic CD that can be combined with lipid/oil: alkylatedβ-cyclodextrin, 2,6-Di-O-ethyl-β-cyclodextrin,2,3,6-Tri-O-ethyl-β-cyclodextrin; acylated β-Cyclodextrin:2,3,6-Tri-O-acyl(C₂-C₁₈)-β-cyclodextrin,2,3,6-Tri-O-butanoyl-3-cyclodextrin, 2,3,6-Tri-O-valeryl-β-cyclodextrin,2,3,6-Tri-O-octyl-β-cyclodextrin,O-Carboxymethyl-O-ethyl-β-cyclodextrin, β-Cyclodextrin sulfate;sulfobutyl ether group-β-cyclodextrin; and sulfobutyl ethergroup-β-cyclodextrin. Studies herein demonstrate that both types ofsolutions are able to provide a significant level of Noble gas in anaqueous-based system. Upon oral delivery these solutions have preventiveeffects in the brain and heart tissues. For example, Xe solutions areshown to increase tolerance of tissues to ischemic damage and providecardio-protective effects. In model systems for heart disease thecompositions are able not only to have a direct positive effect markerof cardiac function (see, e.g., FIG. 12) but are also able to loweroverall blood pressure in mice deficient for Apo-E (results shown inTable 2). Moreover, these solutions also demonstrate biologicallysignificant (therapeutic) effects in model systems for Alzheimer'sdisease. In particular, Xe based compositions are shown effective inreducing β-amyloid load in both the blood and brain tissues of treatedanimals (FIG. 14). Thus, compositions are provided comprising effectiveamounts of dissolved or trapped Ar or Xe that can be used to providecardiovascular and neuroprotective effects to a subject.

The Noble gas compositions and therapeutic methods disclosed hereinoffer new avenues for the increasing wellbeing as well as for thetreatment and prevention of a wide range of chronic diseases.Importantly, the compositions provided herein have been shown to providepotent cardio-protective and blood pressure lowing effects at specificdosages that could be useful in treatment of patients with heart diseaseor who have a high risk of stroke. Likewise, the provided Noble gascompositions are shown able to reduce amyloid load in body tissues andtherefore offer a unique therapy to treat and prevent the onset ofAlzheimer's disease. Given the convenient aqueous formulations that havenow been achieved, effective amounts of non-toxic Noble gases can now beeasily delivered via oral formulations. Given the stability of theformulations a variety of doses could be easily distributed withoutcomplex packaging, dosing systems or even refrigeration that improvewellbeing by increasing or improving certain physiological parameters(e.g. reducing inflammation, reducing stress, increased, relaxation,reducing blood pressure, clearing the mind) at certain dosages totherapeutic/preventives at other dosages (e.g. improved cardiac andneurological function). Accordingly, a range of compositions intendedfor primarily oral delivery including but not limited to beverages couldbe used for gas delivery to provide an effective and convenientnutraceutical or therapeutic that is easily incorporated into standardpreventative therapies such as diet modification and exercise. Moreover,because of the ease of delivery and the lack of toxicity formulations,provided here could likely be administered with little or no supervisionfrom medical professionals.

I. PHARMACEUTICAL AND NUTRACEUTICAL FORMULATIONS

Pharmaceutical and nutraceutical compositions provided herein comprisean effective amount of a tissue or cell protective gas, such as Xe orAr, and, optionally additional agents such as further gases, dissolvedor dispersed in an acceptable carrier can be included. In some aspects,such an acceptable carrier includes components formulated to increase orcontrol the content of soluble gas to desired levels, such as lipidsincluding edible oils or caging molecule as detailed above. The Phrase“containing” means the dissolving, emulsifying, suspending, trapping andother like means of obtaining a solution with Nobel gas for primarilyoral delivery. The phrase “acceptable carrier” refer to molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to (e.g., ingested by) ananimal, such as, for example, a human, as appropriate. The preparationof a pharmaceutical or nutraceutical composition that contains a Noblegas is detailed herein. Further addition of active or inactiveingredients to such a composition will be known to those of skill in theart in light of the present disclosure, and as exemplified byRemington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company,1990, incorporated herein by reference. Moreover, for animal (e.g.,human) administration, it will be understood that preparations shouldmeet sterility, pyrogenicity, general safety and purity standards asrequired by FDA Office of Biological Standards.

An “acceptable carrier” may include any and all solvents, dispersionmedia, coatings, surfactants, antioxidants, preservatives (e.g.,antibacterial agents, antifungal agents), isotonic agents, absorptiondelaying agents, salts, preservatives, drugs, drug stabilizers, gels,binders, excipients, disintegration agents, lubricants, sweeteningagents, flavoring agents, dyes, such like materials and combinationsthereof, as would be known to one of ordinary skill in the art (see, forexample, Remington's Pharmaceutical Sciences, 18th Ed. Mack PrintingCompany, 1990, pp. 1289-1329, incorporated herein by reference). Exceptinsofar as any conventional carrier is incompatible with the activeingredient, its use in the therapeutic or pharmaceutical compositions iscontemplated. In general the carriers of the present embodiments allcomprise an oil-based component that comprises a dissolved Noble gas,such as Ar or Xe.

In certain embodiments, the pharmaceutical composition may comprisedifferent types of carriers depending on whether it is to beadministered in solid, liquid or aerosol form, and whether it need to besterile for such routes of administration as injection. In certainembodiments, pharmaceutical compositions provided herein can beadministered intravenously, intradermally, intraarterially,intraperitoneally, intralesionally, intracranially, intraarticularly,intraprostaticaly, intrapleurally, intratracheally, intranasally,intravitreally, intravaginally, intrarectally, topically,intratumorally, intramuscularly, intraperitoneally, subcutaneously,subconjunctival, intravesicularlly, mucosally, intrapericardially,intraumbilically, intraocularally, orally, topically, locally,inhalation (e.g. aerosol inhalation), injection, infusion, continuousinfusion, localized perfusion bathing target cells directly, via acatheter, via a lavage, in cremes, in lipid compositions (e.g.,liposomes), or by other method or any combination of the forgoing aswould be known to one of ordinary skill in the art (see, for example,Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company,1990, incorporated herein by reference).

In other embodiments, one may use eye drops, nasal solutions or sprays,aerosols or inhalants in the present embodiments. Such compositions aregenerally designed to be compatible with the target tissue type. In anon-limiting example, nasal solutions are usually aqueous solutionsdesigned to be administered to the nasal passages in drops or sprays.Nasal solutions are prepared so that they are similar in many respectsto nasal secretions, so that normal ciliary action is maintained. Thus,in preferred embodiments the aqueous nasal solutions usually areisotonic or slightly buffered to maintain a pH of about 5.5 to about6.5. In addition, antimicrobial preservatives, similar to those used inophthalmic preparations, drugs, or appropriate drug stabilizers, ifrequired, may be included in the formulation. For example, variouscommercial nasal preparations are known and include drugs such asantibiotics or antihistamines.

Additional formulations which are suitable for other modes ofadministration include suppositories. Suppositories are solid dosageforms of various weights and shapes, usually medicated, for insertioninto the rectum, vagina or urethra. After insertion, suppositoriessoften, melt or dissolve in the cavity fluids. In general, forsuppositories, traditional carriers may include, for example,polyalkylene glycols, triglycerides or combinations thereof. In certainembodiments, suppositories may be formed from mixtures containing, forexample, the active ingredient in the range of about 0.5% to about 10%,and preferably about 1% to about 2%.

Sterile injectable solutions can also be prepared by incorporating theactive compounds in the required amount in the appropriate solvent withvarious of the other ingredients enumerated above, as required, followedby filtered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and/or the otheringredients. In the case of sterile powders for the preparation ofsterile injectable solutions, suspensions or emulsion, the preferredmethods of preparation are vacuum-drying or freeze-drying techniqueswhich yield a powder of the active ingredient plus any additionaldesired ingredient from a previously sterile-filtered liquid mediumthereof. The liquid medium should be suitably buffered if necessary andthe liquid diluent first rendered isotonic prior to injection withsufficient saline or glucose. The preparation of highly concentratedcompositions for direct injection is also contemplated, where the use ofDMSO as solvent is envisioned to result in extremely rapid penetration,delivering high concentrations of the active agents to a small area. Inparticular embodiments, prolonged absorption of an injectablecomposition can be brought about by the use in the compositions ofagents delaying absorption, such as, for example, aluminum monostearate,gelatin or combinations thereof.

The composition must be stable under the conditions of manufacture andstorage, and preserved against the contaminating action ofmicroorganisms, such as bacteria and fungi. Where clinical applicationof liposomes (e.g., liposomes comprising gases) is undertaken, solutionsof therapeutic compositions can be prepared in water suitably mixed witha surfactant, such as hydroxypropylcellulose. Dispersions also can beprepared in glycerol, liquid polyethylene glycols, mixtures thereof andin oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms. The therapeutic compositions of the present inventionare advantageously administered in the form of injectable compositionseither as liquid solutions or suspensions; solid forms suitable forsolution in, or suspension in, liquid prior to injection may also beprepared. These preparations also may be emulsified. A typicalcomposition for such purpose comprises a pharmaceutically acceptablecarrier. For instance, the composition may contain 10 mg, 25 mg, 50 mgor up to about 100 mg of human serum albumin per milliliter of phosphatebuffered saline. Other pharmaceutically acceptable carriers includeaqueous solutions, non-toxic excipients, including salts, preservatives,buffers and the like.

Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, vegetable oil and injectable organic esters such as ethyloleate.Aqueous carriers include water, alcoholic/aqueous solutions, salinesolutions, parenteral vehicles such as sodium chloride, Ringer'sdextrose, etc. Intravenous vehicles include fluid and nutrientreplenishers. Preservatives include antimicrobial agents, anti-oxidants,chelating agents and inert gases. The pH and exact concentration of thevarious components the pharmaceutical composition are adjusted accordingto well-known parameters. Additional formulations are suitable for oraladministration. Oral formulations include such typical excipients as,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharine, cellulose, magnesium carbonateand the like. The compositions generally will take the form of solutionsor suspensions.

The therapeutic compositions of the present embodiments may includeclassic pharmaceutical preparations. Administration of therapeuticcompositions according to the present invention will be via any commonroute so long as the target tissue is available via that route. In thiscase, intravenous injection or infusion may be preferred. Suchcompositions would normally be administered as pharmaceuticallyacceptable compositions that include physiologically acceptablecarriers, buffers or other excipients.

Oral Formulations

In certain preferred embodiments, a composition of the embodiments isadministered orally and is formulated to facilitate such oraladministration (e.g., as a beverage formulation). Thus, in someembodiments a composition (such as an emulsion of oil-encapsulated gasor polymer encapsulated gas) may comprise, for example, solutions,suspensions, emulsions, tablets, pills, capsules (e.g., hard or softshelled gelatin capsules), sustained release formulations, buccalcompositions, troches, elixirs, suspensions, syrups, or combinationsthereof. Oral compositions may be incorporated directly with a food ordrink product (e.g., along with a fruit juice or alcohol). Preferredcarriers for oral administration comprise inert diluents, assimilableedible carriers or combinations thereof. In other aspects, the oralcomposition may be prepared as a syrup or elixir. A syrup or elixir, andmay comprise, for example, at least one active agent, a sweeteningagent, a preservative, a flavoring agent, a dye, a preservative, orcombinations thereof.

In further aspects, a composition comprising dissolved Noble gas, suchas Xe or Ar, can be formulated into a capsule or tablet for oraladministration. In some aspects, the capsule is substantiallyimpermeable to gas, and preferably the capsule is formulated to dissolvein the gastrointestinal tract of a subject.

In certain preferred embodiments an oral composition may comprise one ormore binders, excipients, disintegration agents, lubricants, flavoringagents, and combinations thereof. In certain embodiments, a compositionmay comprise one or more of the following: a binder, such as, forexample, gum tragacanth, acacia, cornstarch, gelatin or combinationsthereof; an excipient, such as, for example, dicalcium phosphate,mannitol, lactose, starch, magnesium stearate, sodium saccharine,cellulose, magnesium carbonate or combinations thereof; a disintegratingagent, such as, for example, corn starch, potato starch, alginic acid orcombinations thereof; a lubricant, such as, for example, magnesiumstearate; a sweetening agent, such as, for example, sucrose, lactose,saccharin or combinations thereof; a flavoring agent, such as, forexample peppermint, oil of wintergreen, cherry flavoring, orangeflavoring, etc.; or combinations thereof the foregoing. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, carriers such as a liquid carrier. Various other materialsmay be present as coatings or to otherwise modify the physical form ofthe dosage unit. For instance, tablets, pills, or capsules may be coatedwith shellac, sugar or both.

A composition may comprise various antioxidants to retard oxidation ofone or more component. Additionally, the prevention of the action ofmicroorganisms can be brought about by preservatives such as variousantibacterial and antifungal agents, including but not limited toparabens (e.g., methylparabens, propylparabens), chlorobutanol, phenol,sorbic acid, thimerosal or combinations thereof.

In embodiments where the composition is in a liquid form, a carrier cancomprise a solvent or dispersion medium comprising but not limited to,water, ethanol, polyol (e.g., glycerol, propylene glycol, liquidpolyethylene glycol, etc.), lipids (e.g., triglycerides, vegetable oils,liposomes) and combinations thereof. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin; bythe maintenance of the required particle size by dispersion in carrierssuch as, for example liquid polyol or lipids; by the use of surfactantssuch as, for example hydroxypropylcellulose; or combinations thereofsuch methods. In many cases, it will be preferable to include isotonicagents, such as, for example, sugars, sodium chloride or combinationsthereof.

Additional Components for Pharmaceutical and Nutraceutical Formulations

Oral Noble gas formulations of the embodiments may comprise additionalcomponents as detailed herein below. It is contemplated that suchadditional components may be included, for example, as at least or atmost about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 113, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89or 90% of the total composition on a weight:weight or volume:volumebasis. In certain aspects, an additional component comprises less thanabout 20%, 10%, 5% or less of the total composition on a weight:weightor volume:volume basis.

In some embodiments micronutrients can included, such as (withoutlimitation) L-carnitine, choline, coenzyme Q10, alpha-lipoic acid,omega-3-fatty acids, pepsin, phytase, trypsin, lipases, proteases,cellulases, and a combination comprising at least one of the foregoingmicronutrients.

Antioxidants can include materials that scavenge free radicals. In someembodiments, exemplary antioxidants can include citric acid, rosemaryoil, vitamin A, vitamin E, vitamin E phosphate, tocopherols,di-alpha-tocopheryl phosphate, tocotrienols, alpha lipoic acid,dihydrolipoic acid, xanthophylls, beta cryptoxanthin, lycopene, lutein,zeaxanthin, astaxanthin, beta-carotene, carotenes, mixed carotenoids,polyphenols, flavonoids, and a combination comprising at least one ofthe foregoing antioxidants.

Exemplary nutrients can also include amino acids such as L-tryptophan,L-lysine, L-leucine, L-methionine, 2-aminoethanesulfonic acid (taurine),and L-carnitine; creatine; glucuronolactone; inositol; and a combinationcomprising at least one of the foregoing nutrients.

Phytochemicals (“phytonutrients”) are plant derived compounds which mayprovide a beneficial effect on the health or well-being of the consumer.Phytochemicals include plant derived antioxidants, phenolic compoundsincluding monophenols and polyphenols, and the like. Exemplaryphytochemicals include lutein, lycopene, carotene, anthocyanin,capsaicinoids, flavonoids, hydroxycinnamic acids, isoflavones,isothiocyanates, monoterpenes, chalcones, coumestans, dihydroflavonols,flavanoids, flavanols, quercetin, flavanones, flavones, flavan-3-ols(catechins, epicatechin, epigallocatechin, epigallocatechingallate, andthe like), flavonals (anthocyanins, cyanidine, and the like); phenolicacids; phytosterols, saponins, terpenes (carotenoids), and a combinationcomprising at least one of the foregoing phytochemicals.

The phytochemicals can be provided in substantially pure or isolatedform or in the form of natural plant extracts. Suitable plant extractswhich contain one or more phytochemicals include fruit skin extracts(grape, apple, crab apple, and the like), green tea extracts, white teaextracts, green coffee extract, and a combination comprising at leastone of the foregoing extracts.

Various herbals, aromatic plants or plant parts or extracts thereof, canalso be included in the compositions for a variety of reasons such asfor flavor or for their potential health benefits. Exemplary herbalsinclude Echinacea, Goldenseal, Calendula, Rosemary, Thyme, Kava Kava,Aloe, Blood Root, Grapefruit Seed Extract, Black Cohosh, Ginseng,Guarana, Cranberry, Ginko Biloba, St. John's Wort, Evening Primrose Oil,Yohimbe Bark, Green Tea, Ma Huang, Maca, Bilberry, extracts thereof, anda combination comprising at least one of the foregoing herbals.Additional plant extracts for inclusion in a composition of theembodiments include, but are not limited to, extracts or components fromAcai, Spirulina, Chlorella, Wheat Grass, Black Soy Bean, Turmeric, ChiaSeeds, Coconut Oil, Cocoa, Lingon Berries, Eggs, Beat Juice, MustardGreens, Sweet Potatoes, Red Wine, Avocados, Blue Berries, Black Berries,Almonds, Green Tea, Lentils, Black Beans and Aloe Vera. For example, insome aspects, a composition of the embodiments includes a protein sourceselected from the group consisting of whey protein concentrate,potassium caseinate, egg albumin, soy isolate, and whey isolate, (Brown)rice protein, hydrolyzed beef protein isolate, Pea Protein Isolate, andhemp protein.

In still further aspects, a composition of the embodiment can include adiuretic, such a watermelon extract or dandelion leaf extract (e.g.,4:1).

In some embodiments, the composition can have a Brix measurement asmeasured by a Brix refractometer at 20° C. of about 8.0 to about 9.5°Brix, specifically about 8.5 to about 8.9° Brix. In another embodiment,the composition can have a Brix measurement as measured by a Brixdensitometer at 20° C. of about 7.5 to about 9.1° Brix, specificallyabout 7.9 to about 8.3° Brix.

Electrolytes

The inclusion of electrolytes in the various aspects of the compositionsof the invention is contemplated. Exemplary electrolytes include saltsof a metal of the groups I and II of the periodic table, preferably theinorganic and organic salts of sodium, potassium, calcium and/ormagnesium. Examples of such salts include, but are not limited to, aresodium acetate, acidic sodium citrate, acidic sodium phosphate, sodiumamino salicylate, sodium bicarbonate, sodium bromide, sodium chloride,sodium citrate, sodium lactate, sodium phosphate, sodium salicylate,sodium sulphate (anhydrous), sodium sulphate (Glauber's salt), potassiumacetate, potassium bicarbonate, potassium bromide, potassium chloride,potassium citrate, potassium-D-gluconate, mono- and dibasic potassiumphosphate, calcium acetate, calcium chloride, calcium citrate,calcium-D-gluconate, calcium lactate, calcium laevulinate, dibasiccalcium phosphate, magnesium chloride and magnesium sulfate. In oneaspect, the electrolytes are sodium chloride, monopotassium phosphateand magnesium sulfate and, when present in an 8 oz. volume, are includedin amounts of about 50 mg to about 500 mg, from about 10 mg to about 200mg and from about 10 mg to about 200 mg, respectively. In other aspects,sodium chloride, when present in an 8 oz. volume, is included in anamount ranging from about 50 mg to about 60 mg, about 70 mg, about 80mg, about 90 mg or about 100 mg and magnesium sulfate and monopotossiumphosphate, when present in an 8 oz. volume, are included in amounts ofabout 10 mg to about 20 mg, about 30 mg, about 40 mg, about 50 mg, about60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or about 200mg. Compositions of the embodiments can likewise include glycerol.

Additional electrolytes and liquid formulation for composition areprovides in U.S. Pat. Nos. 4,981,687, 5,089,477, 5,147,650, 5,236,712,and 5,238,684, each of which are incorporated herein by reference.

Vitamins and Minerals

It is contemplated to include vitamin and/or minerals into variousaspects of the compositions of the embodiments. Vitamins for inclusioninclude, but are not limited to, Vitamins and Co-Vitamins such asVitamin A (beta-carotene), Choline, Vitamin B1 (thiamin), Vitamin B2(riboflavin, vitamin G), Vitamin B3 (niacin, vitamin P, vitamin PP),Vitamin B5 (pantothenic acid), Vitamin B6 (pyridoxine, pyridoxamine, orpyridoxal), Vitamin B7 (biotin, vitamin H), Vitamin B9 (folic acid,folate, vitamin M), Vitamin B12 (cobalamin), Vitamin C (ascorbic acid),Vitamin D (ergocalciferol, or cholecalciferol), Vitamin E (tocopherol)and Vitamin K (naphthoquinoids). Minerals for possible inclusioninclude, without limitation, Calcium (Ca), Chloride (Cl—), Chromium(Cr), Cobalt (Co) (as part of Vitamin B12), Copper (Cu), Iodine (I),Iron (Fe), Magnesium (Mg), Manganese (Mn), Molybdenum (Mo), Phosphorus(P), Potassium (K), Selenium (Se), Sodium (Na) and Zinc (Zn).

Vitamin A, for example, helps in the formation and maintenance ofhealthy teeth, skeletal and soft tissue, mucous membranes, and skin. Itis also known as retinol because it generates the pigments that arenecessary for the working of the retina. It promotes good vision,especially in dim light. Beta-carotene is a precursor to vitamin A thathas antioxidant properties, helping the body deal with unstablechemicals called free radicals.

Thiamine (B-1) helps the body cells convert carbohydrates into energy.It is also essential for the functioning of the heart and for healthynerve cells, including those in the brain. Riboflavin (B-2) works withthe other B vitamins and is important for body growth and red blood cellproduction. Similar to thiamine, it helps in releasing energy fromcarbohydrates. Niacin (B-3) is a B vitamin that helps maintain healthyskin and nerves. It is also important for the conversion of food toenergy and may have cholesterol-lowering effects. Vitamin B-6 is alsoknown as pyridoxine and aids in the formation of red blood cells and inthe maintenance of normal brain function. It also assists in thesynthesizing of antibodies in the immune system. Vitamin B-12, like theother B vitamins, is important for metabolism, participating in, forexample, the formation of red blood cells. Pantothenic acid is essentialfor the metabolism of food. It is also essential in the synthesis ofhormones and cholesterol. Biotin is essential for the metabolism ofproteins and carbohydrates, and in the synthesis of hormones andcholesterol. Folate (folic acid) works with vitamin B-12 in theproduction of red blood cells and is necessary for the synthesis of DNA.

Vitamin C, also called ascorbic acid, promotes healthy teeth and gums,helps in the absorption of iron, and helps maintain normal connectivetissue. It also promotes wound healing and is an antioxidant.

Vitamin D promotes the body's absorption of calcium, which is essentialfor the normal development and maintenance of healthy teeth and bones.It also helps maintain adequate blood levels of calcium and phosphorus,which are minerals necessary for many functions.

Vitamin E is also known as tocopherol and is an antioxidant. It is alsoimportant in the formation of red blood cells and the use of vitamin K.

Therefore, it is desirable to incorporate various vitamin types into thevarious aspects of the compositions of the invention. In one embodiment,vitamin B1 (thiamin) when present in an 8 oz. volume, is included in anamount ranging from about 0.1 mg to about 5 mg; vitamin B2 (riboflavin),when present in an 8 oz. volume, is included in an amount ranging fromabout 0.1 mg to about 5 mg; vitamin B3 (niacin), when present in an 8oz. volume, is included in an amount ranging from about 1 mg to about 50mg; vitamin B5 (pantothenoic acid), when present in an 8 oz. volume, isincluded in an amount ranging from about 1 mg to about 50 mg; vitaminB6, when present in an 8 oz. volume, is included in an amount rangingfrom about 0.1 mg to about 5 mg; and vitamin B12, when present in an 8oz. volume, is included in an amount ranging from about 1 μg to about 50μg. In a further embodiment, vitamins B1, B2 and B6, when present in an8 oz. volume, are included in amounts of about 0.1 mg to about 2 mg,about 3 mg, about 4 mg, or about 5 mg; vitamins B3 and B5, when presentin an 8 oz. volume, are included in amounts of 1 mg, to about 3 mg,about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg,about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg; andvitamin B12, when present in an 8 oz. volume, is included in amounts of1 μg to about 10 μg, about 20 μg, about 30 μg, about 40 μg, or about 50μg.

In yet another embodiment, a composition of the invention providedfurther comprising vitamin A, when present in an 8 oz. volume, isincluded in an amount ranging from about 50 IU to about 1000 IU. In oneaspect, vitamin A, when present in an 8 oz. volume, is included inamounts of about 50 IU to about 100 IU, about 200 IU, about 300 IU,about 400 IU, about 500 IU, about 600 IU, about 700 IU, about 800 IU,about 900 IU or about 1000 IU.

In another embodiment, a composition of the embodiments is providedfurther comprising, vitamin C, when present in an 8 oz. volume, isincluded in an amount ranging from about 10 mg to about 100 mg. In someaspects, vitamin C, when present in an 8 oz. volume, is included inamounts of 10 mg to about 20 mg, about 30 mg, about 40 mg, about 50 mg,about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg.

In yet another embodiment, a composition of the invention is providedfurther comprising vitamin E, when present in an 8 oz. volume, isincluded in an amount ranging from about 1 IU to about 50 IU. In aspect,vitamin E, when present in an 8 oz. volume, is included in amounts ofabout 1 IU to about 10 IU, about 20 IU, about 30 IU, about 40 IU, orabout 50 IU.

Amino Acids

In a further embodiment, the aforementioned composition is providedfurther comprising one or more amino acids selected from the groupconsisting of alanine, arginine, creatine, cysteine, glysine, histidine,glutamine, lysine, methionine, ornithine, leucine, isoleucine, serine,tyrosine, aspartagine, aspartic acid, threonine, proline, tryptophan,valine, phenylalanine, and selenocysteine. For example, creatine can besupplied in its various forms such as creatine monohydrate, creatinemagnesium chelate or creatine nitrate.

For example, glutamine, when present in an 8 oz. volume, is included inan amount ranging from about 5 mg to about 100 mg or in amounts of about5 mg to about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg,about 70 mg, about 80 mg, about 90 mg or about 100 mg.

Furthermore, the inclusion of cysteine in a composition of the inventionis contemplated. For example, cysteine, when present in an 8 oz. volume,is included in an amount ranging from about 10 mg to about 100 mg.

Carbohydrates

As mentioned supra, in some aspects including a carbohydrate source inthe composition of the invention is contemplated. Exemplarycarbohydrates include, but are not limited to, monosaccharides, adisaccharides, oligosaccharides and a glucose polymers. Modifiedcarbohydrates, such as sucrolose, are also contemplated. In anotheraspect, carbohydrate of the formulation is derived from citric acid.

Flavoring Agents

One or more flavoring agents may be added to the compositions of theinvention in order to enhance their palatability. Any natural orsynthetic flavor agent can be used in the present invention. Forexample, one or more botanical and/or fruit flavors may be utilizedherein. As used herein, such flavors may be synthetic or naturalflavors.

Exemplary fruit flavors include exotic and lactonic flavors such as, forexample, passion fruit flavors, mango flavors, pineapple flavors,cupuacu flavors, guava flavors, cocoa flavors, papaya flavors, peachflavors, and apricot flavors. Besides these flavors, a variety of otherfruit flavors can be utilized such as, for example, apple flavors,citrus flavors, grape flavors, raspberry flavors, cranberry flavors,cherry flavors, grapefruit flavors, and the like. These fruit flavorscan be derived from natural sources such as fruit juices and flavoroils, or may alternatively be synthetically prepared.

Exemplary botanical flavors include, for example, tea (e.g., black andgreen tea), aloe vera, guarana, ginseng, ginkgo, hawthorn, hibiscus,rose hips, chamomile, peppermint, fennel, ginger, licorice, lotus seed,schizandra, saw palmetto, sarsaparilla, safflower, St. John's Wort,curcuma, cardimom, nutmeg, cassia bark, buchu, cinnamon, jasmine, haw,chrysanthemum, water chestnut, sugar cane, lychee, bamboo shoots,vanilla, coffee, and the like.

The flavor agent can also comprise a blend of various flavors. Ifdesired, the flavor in the flavoring agent may be formed into emulsiondroplets which are then dispersed in the beverage composition orconcentrate. Because these droplets usually have a specific gravity lessthan that of water and would therefore form a separate phase, weightingagents (which can also act as clouding agents) can be used to keep theemulsion droplets dispersed in the beverage composition or concentrate.Examples of such weighting agents are brominated vegetable oils (BVO)and resin esters, in particular the ester gums. See L. F. Green,Developments in Soft Drinks Technology, Vol. 1, Applied SciencePublishers Ltd., pp. 87-93 (1978) (Incorporated herein by reference) fora further description of the use of weighting and clouding agents inliquid beverages. Typically the flavoring agents are conventionallyavailable as concentrates or extracts or in the form of syntheticallyproduced flavoring esters, alcohols, aldehydes, terpenes,sesquiterpenes, and the like.

The amount of flavor agent used will vary, depending on the agents usedand the intensity desired in the finished product. The amount can bereadily determined by one skilled in the art. Generally, if utilized,the flavor agent should be present at a level of from about 0.0001% toabout 0.5%.

Flavanols

Flavanols are natural substances present in a variety of plants (e.g.,fruits, vegetables, and flowers). The flavanols which may be utilized inthe present invention can be extracted from, for example, fruit,vegetables, green tea or other natural sources by any suitable methodwell known to those skilled in the art. Flavanols may be extracted fromeither a single plant or mixtures of plants. Plants containing flavanolsare known to those skilled in the art.

The amount of flavanols in the various aspect of the compositions of theinvention can vary. However, wherein one or more flavanols are utilized,preferably from about 0.001% to about 5% by weight of the composition.

Sensate Formulations

In some aspects, compositions include “sensates”, trigeminal nervestimulants which can alter the taste of e.g., a beverage composition anddecrease the perception of off-notes. Sensates include “warming agents”,compounds which provide a sensation of warmth; “cooling agents”,compounds which provide a cooling sensation; and “tingling agents”,compounds which provide a tingling, stinging or numbing sensation. Thesensate may be a warming, a cooling, a tingling agent, or anycombination comprising at least one of the foregoing sensates.

Warming agents may be selected from a wide variety of compounds known toprovide the sensory signal of warming to the individual user. Thesecompounds offer the perceived sensation of warmth, particularly in theoral cavity, and often enhance the perception of flavors, sweeteners andother organoleptic components. Useful warming agents include thosehaving at least one allyl vinyl component, which may bind to oralreceptors. Examples of suitable warming agents include vanillyl alcoholn-butyl ether (TK-1000, supplied by Takasago Perfumery Company Ltd.,Tokyo, Japan); vanillyl alcohol n-propyl ether; vanillyl alcoholisopropyl ether; vanillyl alcohol isobutyl ether; vanillyl alcoholn-amino ether; vanillyl alcohol isoamylether; vanillyl alcohol n-hexylether; vanillyl alcohol methyl ether; vanillyl alcohol ethylether;gingerol; shogaol; paradol; zingerone; capsaicin; dihydrocapsaicin;nordihydrocapsaicin; homocapsaicin; homodihydrocapsaicin; ethanol;isopropyl alcohol; iso-amyl alcohol; benzyl alcohol; glycerine;chloroform; eugenol; cinnamon oil; cinnamic aldehyde; phosphatederivatives thereof, and the like, or a combination comprising at leastone of the foregoing warming sensates.

A variety of well-known cooling agents may be employed in instantcompositions. Exemplary cooling agents include menthol, xylitol,erythritol, menthane, menthone, menthyl acetate, menthyl salicylate,N,2,3-trimethyl-2-isopropyl butanamide (WS-23),N-ethyl-p-menthane-3-carboxamide (WS-3), menthyl succinate,3,1-menthoxypropane 1,2-diol and glutarate esters, among others, and thelike, or a combination comprising at least one of the foregoing coolingsensates.

Tingling agents may be employed in the beverage compositions to providea tingling, stinging or numbing sensation to the user. Exemplarytingling agents include Jambu Oleoresin or para cress (Spilanthes sp.),in which the active ingredient is Spilanthol; Japanese pepper extract(Zanthoxylum peperitum), including the ingredients known as Saanshool-I,Saanshool-II and Sanshoamide; black pepper extract (piper nigrum),including the active ingredients chavicine and piperine; Echinaceaextract; Northern Prickly Ash extract; red pepper oleoresin; and thelike, or a combination comprising at least one of the foregoing tinglingsensates.

A sensate may be present in a composition, such as a composition (e.g.,a beverage composition), in an amount of about 0.01 to about 10 weightpercent, specifically about 0.1 to about 5.0, and yet more specificallyabout 1.0 to about 3.0 weight percent based on the total weight of thebeverage composition.

Stimulants

In some aspects, a composition of the embodiments includes a stimulantor an agent that provides a feeling of enhanced energy level. Forexample, a composition can include Caffeine (anhydrous), Green TeaExtract (Camellia sinensis) (leaf, e.g., 45% EGCG), Hoodia gordonii,Advantra Z® (Citrus aurantium, e.g., 60% synephrine alkaloids),L-Taurine, Panax Ginseng Powder, Glucuronolactone, Adenosine,Octopamine, L-Carnitine, Yohimbine, Vinpocetine, NADH, EvodiamineCinnulin PF® Cinnamon Bark Extract (Cinnamonum burmannii), Banaba LeafExtract, or Zychrome® [Chromium (as Chromium Dinicocysteinate).

Coloring Agent

Small amounts of one or more coloring agents may be utilized in thecompositions of the present invention. FD&C dyes (e.g., yellow #5, blue#2, red #40) and/or FD&C lakes are preferably used. By adding the lakesto the other powdered ingredients, all the particles, in particular thecolored iron compound, are completely and uniformly colored and auniformly colored beverage mix is attained. Preferred lake dyes whichmay be used in the present invention are the FDA-approved Lake, such asLake red #40, yellow #6, blue #1, and the like. Additionally, a mixtureof FD&C dyes or a FD&C lake dye in combination with other conventionalfood and food colorants may be used. Riboflavin and b-carotene may alsobe used. Additionally, other natural coloring agents may be utilizedincluding, for example, fruit, vegetable, and/or plant extracts such asgrape, black currant, aronia, carrot, beetroot, red cabbage, andhibiscus.

The amount of coloring agent used will vary, depending on the agentsused and the intensity desired in the finished product. The amount canbe readily determined by one skilled in the art. Generally, if utilized,the coloring agent should be present at a level of from about 0.0001% toabout 0.5%, preferably from about 0.001% to about 0.1%, and mostpreferably from about 0.004% to about 0.1%, by weight of thecomposition.

Preservatives

Preservatives may or may not be needed for use in the presentcompositions. Techniques such as aseptic and/or clean-fill processingmay be utilized to avoid preservatives. One or more preservatives may,however, optionally be added to the present compositions. Preferredpreservatives include, for example, sorbate, benzoate, and polyphosphatepreservatives (for example, sodium hexametapolyphosphate).

Preferably, wherein a preservative is utilized herein, one or moresorbate or benzoate preservatives (or mixtures thereof) are utilized.Sorbate and benzoate preservatives suitable for use in the presentinvention include sorbic acid, benzoic acid, and salts thereof,including (but not limited to) calcium sorbate, sodium sorbate,potassium sorbate, calcium benzoate, sodium benzoate, potassiumbenzoate, and mixtures thereof.

Wherein a composition comprises a preservative, the preservative ispreferably included at levels from about 0.0005% to about 0.5%, morepreferably from about 0.001% to about 0.4% of the preservative, stillmore preferably from about 0.001% to about 0.1%, even more preferablyfrom about 0.001% to about 0.05%, and most preferably from about 0.003%to about 0.03% of the preservative, by weight of the composition.Wherein the composition comprises a mixture of one or morepreservatives, the total concentration of such preservatives ispreferably maintained within these ranges.

Acidulants

If desired, the present compositions may optionally comprise one or moreacidulants. An amount of an acidulant may be used to maintain the pH ofthe composition. Compositions of the present invention, in variousaspects, have a pH of from about 2 to about 9, from about 2.5 to about8.5, from about 3 to about 8, from about 03.5 to about 7.5, from about 4to about 7, from about 4.5 to about 6.5, or from about 5 to about 6.

Acidity of a composition can be adjusted to and maintained within therequisite range by known and conventional methods, e.g., the use of oneor more of the aforementioned acidulants. Typically, acidity within theabove recited ranges is a balance between maximum acidity for microbialinhibition and optimum acidity for the desired beverage flavor.

Organic as well as inorganic edible acids may be used to adjust the pHof the beverage, and may be added additional to the acid serving as partof the second component herein. The acids can be present in theirundissociated form or, alternatively, as their respective salts, forexample, potassium or sodium hydrogen phosphate, potassium or sodiumdihydrogen phosphate salts. The preferred acids are edible organic acidswhich include citric acid, malic acid, fumaric acid, adipic acid,phosphoric acid, gluconic acid, tartaric acid, ascorbic acid, aceticacid, phosphoric acid or mixtures thereof. The most preferred acids arecitric and malic acids.

The acidulant can also serve as an antioxidant to stabilize beveragecomponents. Examples of commonly used antioxidant include but are notlimited to ascorbic acid, EDTA (ethylenediaminetetraacetic acid), andsalts thereof.

The amount of acidulant used will vary, depending on the agent used andthe pH desired in the finished product. The amount can be readilydetermined by one skilled in the art. Generally, if utilized, theacidulant should be present at a level of from about 0.0001% to about0.5% by weight of composition.

Antioxidants

A composition of the embodiment may, in some aspects, further comprisean antioxidant. For example, the antioxidant may be natural orsynthetic. Suitable antioxidants include, but are not limited to,ascorbic acid and its salts, ascorbyl palmitate, ascorbyl stearate,anoxomer, N-acetylcysteine, benzyl isothiocyanate, o-, m- or p-aminobenzoic acid (o is anthranilic acid, p is PABA), butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), caffeic acid,canthaxantin, alpha-carotene, beta-carotene, beta-carotene,beta-apo-carotenoic acid, carnosol, carvacrol, cetyl gallate,chlorogenic acid, citric acid and its salts, clove extract, coffee beanextract, p-coumaric acid, 3,4-dihydroxybenzoic acid,N,N′-diphenyl-p-phenylenediamine (DPPD), dilauryl thiodipropionate,distearyl thiodipropionate, 2,6-di-tert-butylphenol, dodecyl gallate,edetic acid, ellagic acid, erythorbic acid, sodium erythorbate,esculetin, esculin, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline, ethylgallate, ethyl maltol, ethylenediaminetetraacetic acid (EDTA),eucalyptus extract, eugenol, ferulic acid, flavonoids (e.g., catechin,epicatechin, epicatechin gallate, epigallocatechin (EGC),epigallocatechin gallate (EGCG), polyphenol epigallocatechin-3-gallate),flavones (e.g., apigenin, chrysin, luteolin), flavonols (e.g.,datiscetin, myricetin, daemfero), flavanones, fraxetin, fumaric acid,gallic acid, gentian extract, gluconic acid, glycine, gum guaiacum,hesperetin, alpha-hydroxybenzyl phosphinic acid, hydroxycinammic acid,hydroxyglutaric acid, hydroquinone, N-hydroxysuccinic acid,hydroxytryrosol, hydroxyurea, lactic acid and its salts, lecithin,lecithin citrate; R-alpha-lipoic acid, lutein, lycopene, malic acid,maltol, 5-methoxy tryptamine, methyl gallate, monoglyceride citrate;monoisopropyl citrate; morin, beta-naphthoflavone, nordihydroguaiareticacid (NDGA), octyl gallate, oxalic acid, palmityl citrate,phenothiazine, phosphatidylcholine, phosphoric acid, phosphates, phyticacid, phytylubichromel, pimento extract, propyl gallate, polyphosphates,quercetin, trans-resveratrol rice bran extract, rosemary extract,rosmarinic acid, sage extract, sesamol, silymarin, sinapic acid,succinic acid, stearyl citrate, syringic acid, tartaric acid, thymol,tocopherols (i.e., alpha-, beta-, gamma- and delta-tocopherol),tocotrienols (i.e., alpha-, beta-, gamma- and delta-tocotrienols),tyrosol, vanilic acid, 2,6-di-tert-butyl-4-hydroxymethylphenol (i.e.,lonox 100), 2,4-(tris-3′,5′-bi-tert-butyl-4′-hydroxybenzyl)-mesitylene(i.e., lonox 330), 2,4,5-trihydroxybutyrophenone, ubiquinone, tertiarybutyl hydroquinone (TBHQ), thiodipropionic acid, trihydroxybutyrophenone, tryptamine, tyramine, uric acid, vitamin K and derivates,resveratrol, CoQ-10 (coenzyme Q10), vitamin C, vitamin E, beta-carotene,other related carotenoids, selenium, manganese, glutathione, lipoicacid, flavonoids, phenols, polyphenols, phytoestrogens, N-AcetylCysteine, wheat germ oil, zeaxanthin, or combinations thereof. Preferredantioxidants include tocopherols, ascorbyl palmitate, ascorbic acid, androsemary extract. The concentration of the additional antioxidant orcombination of antioxidants may range from about 0.001% to about 5% byweight, and preferably from about 0.01% to about 1% by weight.

Water

The compositions of the invention may comprise from 0% to about 99.999%water, by weight of the composition. The compositions may comprise atleast about 4% water, at least about 20% water, at least about 40%water, at least about 50% water, at least about 75% water, and at leastabout 80% water. The water included at these levels includes all addedwater and any water present in combination components, for example,fruit juice.

In various embodiments, the composition is provided in an 1 oz volume,about 2 oz, about 3 oz, about 4 oz, about 5 oz, about 6 oz, about 7 oz,about 8 oz, about 9 oz, about 10 oz, about 12 oz, about 14 oz, about 16oz, about 18 oz, about 20 oz, about 22 oz, about 24 oz, about 30 oz, orabout 40 oz volume or in that volume of water. In one aspect, a watercomponent of the formulation is demineralized water.

Alcohol

In some aspects, a beverage composition of the embodiments includesethanol, such as between about 1% to 60% alcohol (ABV), or about 1 to40% alcohol (ABV), or about 1% to 20% alcohol (ABV), or about 1% to 10%alcohol (ABV) (alcohol by volume, ABV). For example, the composition mayinclude distilled spirits, e.g. vodka, rum, whiskey, gin, burbon, rye,or other sweetened or unsweetened distilled liquors. In some aspects,the beverage may be composed of substantial amount of beer, wine, cideror malt liquor.

Sea Minerals

In some aspects, compositions of the embodiments further comprise seaminerals. Sea minerals are nature's perfect balance of macrominerals,microminerals, and ultra trace minerals. They are present in the mostreadily assimilated and bio-available form known. Sea mineral levels arealmost identical to the mineral levels found in human blood serum andare in pH balance very similar to human blood. Sea minerals are free oftoxic heavy metals, such as arsenic, cadmium, mercury, lead, radon,ruthenium, and uranium.

Sea salt, for example, is primarily composed of the following ions,listed in order of descending abundance by weight: Chloride (Cl⁻) 55.03%Sodium (Na⁺) 30.59% Sulfate (SO₄ ²⁻) 7.68% Magnesium (Mg²⁺) 3.68%Calcium (Ca²⁺) 1.18% Potassium (K⁺) 1.11% Bicarbonate (HCO₃ ⁻) 0.41%Bromide (Br) 0.19% Borate (BO₃ ³⁻) 0.08% Strontium (Sr²⁺) 0.04% otherions 0.01%. Sea salt allows liquids to freely cross body membranes,e.g.: the glomeruli of the kidney or blood vessel walls. Sea salt isnecessary for the proper breakdown of plant carbohydrates into usableand assimilable nutrients.

Lipid Components

As further detailed below compositions of the embodiments may furthercomprise a lipid component alone or as part of an oil (such as a lipidcomponent that comprises dissolved Noble gas). Lipids for inclusion incompositions of the embodiments include, but are not limited to ω-3fatty acids such as α-linolenic acid (ALA, 18:3), eicosapentaenoic acidor EPA (20:5n-3), docosahexaenoic acid or DHA (22:6n-3); ω-6 fatty acidssuch as linoleic acid or (LA, 18:2), an omega-6 fatty acid,gamma-linolenic acid or GLA (18:3n-6), dihomo-gamma-linolenic acid orDGLA (20:3n-6) or arachidonic acid or AA (20:4n-6) or ω-9 fatty acids.For example, polyunsaturated oils can be derived from Walnuts, CanolaOil, Sunflower Seeds, Sesame Seeds, Chia Seeds, Peanuts, Peanut Butter,Olive Oil, Seaweed, Sardines, Soybeans, Tuna, Wild Salmon or a WholeGrain Wheat, any of which may be used in a composition of theembodiments.

II. DOSING FOR NOBLE GAS FORMULATIONS

The amount of a Noble gas incorporated into the compositions of theembodiments depend upon the specific formulation used and its intendeduse. An effective amount of the composition is determined based on theintended goal, such to provide neuro- or cardiovascular protectectiveeffect or to provide and improve feeling of well-being to a subject(e.g., reduce inflammation, stress and/or blood pressure). The term“unit dose” or “dosage” refers to physically discrete units suitable foruse in a subject, each unit containing a predetermined-quantity of thecomposition calculated to produce the desired effect. The quantity of acomposition to be administered will also depend, both on the frequencyof administration and unit dose, depends on the protection desired.

In certain embodiments, the actual dosage amount of a compositionprovided to a subject can be determined by physical and physiologicalfactors such as body weight, health condition, previous or concurrenttherapeutic interventions, diet, and on the route of administration.

An effective dose range of a nutraceutical or therapeutic can beextrapolated, for example, from effective doses determined in animalstudies. In general a human equivalent dose (HED) in mg/kg can becalculated in accordance with the following formula (see, e.g.,Reagan-Shaw et al., FASEB J., 22(3):659-661, 2008, which is incorporatedherein by reference):

HED (mg/kg)=Animal dose (mg/kg)×(Animal K _(m)/Human K _(m))

Use of the K_(m) factors in conversion results in more accurate HEDvalues, which are based on body surface area (BSA) rather than only onbody mass. K_(m) values for humans and various animals are well known.For example, the K_(m) for an average 60 kg human (with a BSA of 1.6 m²)is 37, whereas a 20 kg child (BSA 0.8 m²) would have a K_(m) of 25.K_(m) for some relevant animal models are also well known, including:mice K_(m) of 3 (given a weight of 0.02 kg and BSA of 0.007); hamsterK_(m) of 5 (given a weight of 0.08 kg and BSA of 0.02); rat K_(m) of 6(given a weight of 0.15 kg and BSA of 0.025) and monkey K_(m) of 12(given a weight of 3 kg and BSA of 0.24).

For example, in a mouse system it is possible to administer betweenabout 200 μl to 5 ml of orally ingested aqueous solution saturated withXe per day (i.e., about 0.12-3.0 mg/day or about 7.2 to about 180mg/Kg/day for a mouse). Thus, for a human subject that would translateto a dosage of about 500 μg/kg/day to about 12.2 mg/kg/day or for ahuman of average mass (60 kg) that would be about 30 to about 732mg/day.

As noted above, the precise amounts of an active gas component depend onthe particular formulation. Nonetheless, a calculated HED dose canprovide a general guide for dosing that may provide beneficial effects.For the instant embodiments, it is envisioned that the amount of gas,such as Xenon, to be provided in a unit dosage would be from about 0.1to about 200 mg, considering application of 1-2 doses a day to a anaverage subject. For example, one ˜6 oz. cold bottle of aqueous Xe drink(e.g., comprising cyclodextrin encapsulated Xe) could comprise 4 gramsof Xe, while 2 ml of Xe in water at room temperature and 1 atm pressurewould comprise 1.2 mg of Xe. In general, oil formulations of Xe cancomprise about 20 times more Xe than water (without an encapsulationsystem. For example, at room temperature and 1 atm, solutions of about12 mg Xe/ml could be achieved in an oil, such as olive oil.

III. NOBLE GAS ENCAPSULATION

Oil Components

Certain aspects of the embodiments concern oils that comprise dissolvedgases, such as, Ar or Xe. In some aspects the oil is a flaxseed oil,rapeseed oil, soybean oil, walnut oil, fish oil, safflower oil,sunflower oil, avocado oil, coconut oil, corn oil, cotton seed oil,peanut oil, palm oil, olive oil, chia oil, echium oil, krill oil orvegetable oil. In further aspects, the oil is a mixture of two or moreoils. It will be understood by the skilled artisan that the oil ispreferable an edible, substantially non-toxic oil. Thus, in someaspects, the oil is a non-petroleum based oil, such as an animal orvegetable-derived oil. Preferably the oil comprises a high concentrationof omega-3 omega-6- and/or omega-9-fatty fatty acids (e.g.,eicosapentaenoic acid, docosahexaenoic acid, stearidonic acid, and/orlinolenic acid). In still further aspects, an oil is selected for itsconcentration of polyunsaturated fatty acids (PUFA), such as oil havingat least about 5%, 10%, 20% or more PUFA content.

In certain aspects, oil compositions or emulsions of the embodimentscomprise one or more phospholipid component. Phospholipids include, forexample, phosphatidylcholines, phosphatidylglycerols,phosphatidylethanolamines glycerophospholipids and certainsphingolipids. Thus, phospholipids for use herein include, but are notlimited to, dioleoylphosphatidylycholine (“DOPC”), eggphosphatidylcholine (“EPC”), dilauryloylphosphatidylcholine (“DLPC”),dimyristoylphosphatidylcholine (“DMPC”), dipalmitoylphosphatidylcholine(“DPPC”), distearoylphosphatidylcholine (“DSPC”),1-myristoyl-2-palmitoyl phosphatidylcholine (“MPPC”),1-palmitoyl-2-myristoyl phosphatidylcholine (“PMPC”),1-palmitoyl-2-stearoyl phosphatidylcholine (“PSPC”),1-stearoyl-2-palmitoyl phosphatidylcholine (“SPPC”),dilauryloylphosphatidylglycerol (“DLPG”),dimyristoylphosphatidylglycerol (“DMPG”),dipalmitoylphosphatidylglycerol (“DPPG”), distearoylphosphatidylglycerol(“DSPG”), distearoyl sphingomyelin (“DSSP”),distearoylphophatidylethanolamine (“DSPE”), dioleoylphosphatidylglycerol(“DOPG”), dimyristoyl phosphatidic acid (“DMPA”), dipalmitoylphosphatidic acid (“DPPA”), dimyristoyl phosphatidylethanolamine(“DMPE”), dipalmitoyl phosphatidylethanolamine (“DPPE”), dimyristoylphosphatidylserine (“DMPS”), dipalmitoyl phosphatidylserine (“DPPS”),brain phosphatidylserine (“BPS”), brain sphingomyelin (“BSP”),dipalmitoyl sphingomyelin (“DPSP”), dimyristyl phosphatidylcholine(“DMPC”), 1,2-distearoyl-sn-glycero-3-phosphocholine (“DAPC”),1,2-diarachidoyl-sn-glycero-3-phosphocholine (“DBPC”),1,2-dieicosenoyl-sn-glycero-3-phosphocholine (“DEPC”),dioleoylphosphatidylethanolamine (“DOPE”), palmitoyloeoylphosphatidylcholine (“POPC”), palmitoyloeoyl phosphatidylethanolamine(“POPE”), lysophosphatidylcholine, lysophosphatidylethanolamine, anddilinoleoylphosphatidylcholine.

In addition to solublization of Noble gases in lipid components (e.g.,for emulsification) it is also contemplated that such gases can beprovided in an aqueous formulation encapsulated in a liposome. Suchliposome encapsulation of gas has been previously demonstrated, see,e.g., U.S. Pat. No. 7,976,743, incorporated herein by reference.

Water Soluble Molecules

As detailed further herein, in certain aspects, Noble gas solubility inan aqueous component is enhanced by encapsulating the gas (gases) in awater soluble molecule such as polymer. In general the molecule used forencapsulation will be a molecule that can form a pocket with increasedhydrophobicity that is configured so encompass (at portion of) a Noblegas atom. Such an encapsulting molecule thereby shields the hydrophobicatom from the surrounding polar environment of the aqueous componentthereby effectively increasing the content of Noble gas that can besolubilized in the aqueous component.

For example, as shown herein cyclodextrin and its derivatives arewell-adapted for encapsulating Noble gas. In the case of the large Xeatom, β-cyclodextrin was used to encapsulate Xe (see, e.g., FIG. 10B).Theoretically, one skilled in the art could increase the concentrationof cyclodextrin or Hydroxypropyl-beta-cyclodextrin (hp-beta-CD) or otherderivatives to increase the amount of included Xe (i.e. molecular cagedXe). An acceptably safe dose for cyclodextrin can be about 1,000mg/kg/day for chronic oral administration. Solubility of hp-beta-CD, forexample, is 330 mg/ml. That means one can increase cyclodextrinconcentration significantly to about 0.5 mg/ml by use of solublederivatives (See Example 3 and 4). This will be able to bring dissolvedgas concentration to at least 500 mg/ml. Additional molecules that arecontemplated for gas encapsulation include, without limitation, carcerand or hemicarcerands (see, Saleh 2007), macroglobulin, cucurbituril(see, US 20030140787, incorporated herein by reference), calixarenes(Adams et al., 2008), pillararenes (Cao et al., 2009), prophyrins,metallacrowns, crown ethers, cyclotriveratrylenes, crypotophenes,foldamers, additional cyclodextrin polymers, silsesquioxanes (Skelton etal., 2013), tenas porous polymer, HayeSep® Porous Polymer and Porapak™Porous Polymer (reach of the foregoing citations incorporated herein byreference). Selection of the particular polymer for encapsulation willdepend not only on the Noble gas to be encapsulated, but also theparticular type of formulation to be made (e.g., an oral formulation).

IV. EXAMPLES

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

Example 1 Methods for Studies of Example 2

Preparation of Xe-Rich-Solution.

Xenon-rich-solution was composed of olive oil (or can be made with otheroils such as flaxseed oil, rapeseed oil, soybean oil, walnut oil, fishoil etc), egg phosphocholine (Avanti, polar lipid. Alabama, USA), BSA(or other protein such as milk), and lithocholic acid (Sigma-Aldrich,St. Louis, Mo., USA). The solution, comprising 25% oil component, wasemulsified using a sonication method and stabled by fabrication of theemulsion with surfactants such as phospholipids (egg PC, soybean PC,DPPC, DOPC etc), proteins and lithocholic acid. Xenon (MathesonTri-Gas®, Houston, Tex., USA) was saturated into oil by pressurizationat low temperature.

Murine Experiment Setting.

All animal studies were approved by the Animal Welfare Committee at TheUniversity of Texas Health Science Center at Houston. C57BL/6J wild type(WT) and apolipoprotein-E (Apo E) knockout (KO) mice were purchased fromJackson Laboratory (Bar Harbor, Me., USA), see, e.g., Meir et al., 2004,incorporated herein by reference. The control WT mice used wereC57BL/6J, which share the same genetic background with the Apo E KOmice. Six- to eight-month-old male WT and KO mice were fed control orhigh fat diet (Harlan Laboratories, USA) and administered control orXe-rich solution (200 μl, once a day) and -water drink for 6 weeks,since the Apo E KO mice type fed a high fat diet develop atheroscleroticlesions. See FIG. 8.

Echocardiographic Measurements and Electrocardiographic Images (InVivo).

Baseline measurements by echocardiography were obtained before feedingwith the high fat diet. Cardiac morphology and function were assessed byserial M-mode echocardiography using a Vevo 770 Imaging System(VisualSonics Inc., Ontario, Canada) equipped with a 30 MHz microprobe.M-mode ventricular measurements were taken at 6-weeks after the feeding.Electrocardiographic (ECG) data was obtained. Echo data (HR, heart rate;LVID, left ventricular internal dimension; IVS, intra-ventricularseptum; LVPW, left ventricular posterior wall; FS, fractionalshortening; SV, stroke volume; EF, ejection fraction; CO, cardiacoutput; LV Vol, LV volume; LV mass corrected) were analyzed with theanalysis software (VisualSonics Inc., Ontario, Canada).

Protein Assays.

Fresh frozen heart and brain tissues were slightly thawed on crushed iceto allow dissection of the hearts and brains. Tissue samples werehomogenized by sonicating for 2-3 bursts of 20 seconds on ice using aminimal volume of radioimmunoprecipitation assay (RIPA) buffer (CellSignaling Technology, Inc., MA, USA) containing protease inhibitors(complete protease inhibitor cocktail, Sigma) and centrifuged for 10 minat 4° C. at 14,000×g. The supernatant was removed. The proteinconcentration was determined using a Bradford Protein Assay (Bio-Rad,CA, USA).

Brain-Derived Neurotrophic Factor (BDNF) and β-Amyloid Measurements.

Except for the heart and brain extracts, the samples (such as plasma)were thawed and clarified at 12,000 rpm for 10 min at 4° C. prior toELISA assays for β-amyloid per the manufacturer's instructions. BDNF andβ-amyloid peptide (Aβ1-40) content were determined by using BDNFSandwich ELISA Kit (Millipore Corporation, MA, USA) and a Mouse/RatAmyloid β (1-40) High Specific ELISA Assay Kit (IBLAmerican,Minneapolis, Minn., USA). Following instructions, the samples were addedin the pre-coated 96-well microtiter plates for incubation overnight at4° C. After washing, the antibodies were added and incubated.Fluorescence was measured by using SpectroMax Microplate reader (Bio-TekInstruments) at 450 nm. All samples were analyzed in duplicate.

Rat Experiment Setting.

Male Sprague-Dawley rats (260-280 g, Harlan Laboratories Inc.,Indianapolis, Ind.) were randomly divided into two groups (n=8 in eachgroup). One group was given water via a gastric tube and the other giventhe xenon-rich solution. After two weeks, the rats underwent middlecerebral occlusion for 2 hours in a double blind manner. Behavioralfunction was evaluated and then after scarifice, infarct volumes wereevaluated at 24 hours after brain injury under a double blind manner.See FIG. 9.

Rat Model of Middle Cerebral Artery Occlusion (MCAO).

Cerebral ischemia was induced by occluding the right middle cerebralartery (MCA) for 2 hours using the intraluminal suture method. In brief,the right common carotid artery (CCA) was exposed under an operatingmicroscope. The external carotid artery was ligated close to its distalend. The internal carotid artery (ICA) was isolated and separated fromadjacent tissues. A 4-0 monofilament nylon suture (Ethicon, Somerville,N.J., USA) coated with poly L-lysine (0.1% [wt/vol]) and heparin (1000U/mL) was inserted into the MCA lumen located 18 to 20 mm from theexternal carotid artery/common carotid artery bifurcation for 2 hours toprovoke ischemia. As soon as the suture was removed, external carotidartery was ligated, allowing blood reperfusion through common carotidartery into MCA. In all experiments, body temperature was monitored andmaintained at 37° C. during ischemia and over the first hour ofreperfusion with the use of a feed-forward temperature controllerequipped with a heating lamp and heating pad (Harvard Apparatus,Holliston, Mass., USA). A polyethylene catheter was introduced into theright femoral artery for pressure recording. Cerebral blood flow wasmonitored with the use of a PR407-1 straight-needle laser Dopplerflowmeter probe (Perimed, Järfalla, Stockholm, Sweden) connected to astandard laser Doppler monitor (PF5010 LDPM unit and PF5001 main unit;Perimed, Järfalla, Stockholm, Sweden). Interruption of blood flow wasrecorded in the region of ischemic penumbra (2 mm lateral and 2 mmposterior to the bregma).

Neurologic Assessment.

Neurologic assessment was conducted at 24 hours after brain injury. Allbehavioral tests were conducted in a quiet and low-lit room by anobserver blinded with respect to the treatment groups. Animals weretested for motor function and neurologic outcomes by recording limbplacement, beam walking, and grid walking abilities.

Infarct Volume Measurement.

After neurologic assessment at 24 hours after surgery, animals weresacrificed and the brains harvested. Using a Jacobowitz brain slicer,2-mm thick coronal sections were stained with 2% TTC. Infarct size wasnormalized with respect to the whole brain volume and presented asnormalized infarct volume (%).

Statistical Analysis.

Data were processed using Microsoft Excel and GraphPad Prism 5.0. Allvalues are expressed as the mean±S.E.M. Comparisons between each of twogroups was determined using the unpaired 2-tailed Student's t test.Analysis of multiple groups was performed using one-way ANOVA, followedby a Tukey's post hoc multiple comparison test. P values of less than0.05 were considered significant.

Example 2 Xe Administration Studies

Resistance to Cardiac Hypertrophy in Response to Xenon (Xe) Exposure.

To examine the effect of Xe activity on heart disease an apolipoproteinE knockout (apoE−/−; or “KO” as used herein) mouse model was employed.This is a well-established model for atheriosclerosis, as the animalswill develop atherosclerotic lesions even on a normal chow diet, while ahigh fat diet significantly accelerates this process (Meir et al.,2004). Accordingly, the model has previously been successfully employedto evaluate the effects of both natural compounds and pharmaceuticals onatheriosclerosis and cardiovascular disease.

Animals were divided into 5 groups (see experiment setting).Echocardiography was used to assess cardiac dimensions and function atbaseline, and at 6-weeks following the Xe exposure (FIGS. 1 and 2; Table1). Cardiac size of WT and KO hearts were determined with LV mass(corrected) and normalized to body weight (mg/g) following 6-weeks ofthe Xe exposure (FIG. 3A).

As expected, LV mass increased in Apo E KO mice fed with/without highfat diet at 6-weeks and baseline versus WT and WT after 6 weeks,respectively. The increase in LV mass was blocked in KO mice treatedwith Xe (KO6w Xe) as compared to the KO6w vehicle and KO6w controlgroups. The presence of a hypertrophic heart was confirmed in that heartweight normalized to body weight was significantly increased in the KO6wcontrol and vehicle groups. Decreased heart-to-body weight was observedin the KO6w Xe mice in response to the Xe exposure at 6 weeks, comparedto the KO6w vehicle (FIG. 3B).

Intra-ventricular septum (IVS), LV posterior wall thickness (PW), LVvolume (V), and LV internal dimensions (ID) were measured byechocardiography at baseline and following 6 weeks of Xe exposure adiastole and systole, in WT and ApoE-KO hearts (FIG. 1 and Table 1). Thein wall thickness increase was significantly blocked in KO6w Xe mice inresponse to Xe exposure at 6 weeks, as compared to the KO6w vehiclemice, as well as versus KO6w/control mice (FIGS. 1A and 1B). Heart rate(HR) increased in KO/KO6w/control/vehicle animals compared to WT andWT6w, respectively. Again, this increase was blocked in KO6w given Xe(representative M-mode data are shown in FIG. 4A). Taken together, theseresults indicate that Xe activity suppresses progression of cardiachypertrophy.

Improved Cardiac Function and Myocardial Ischemia in Response to XeExposure.

Cardiac function was assessed at baseline and 6 weeks following Xeexposure (FIG. 2). At baseline and 6 weeks, LV fractional shortening(FS), LV ejection fraction (EF), and cardiac output (CO) were decreasedin KO mice fed with/without high fat diet, as compared to WT and WT6w,respectively. On the other hand, KO6w Xe hearts, in response to Xeexposure, significantly blocked these decreases at 6 week time point ascompared to KO6w vehicle (FIGS. 2A-C; respectively).

ECG data show changes in T wave, ST segment, and QRS complex inKO/KO6w/control/vehicle hearts compared to WT/WT6w, respectively,consistent with myocardial ischemia. However, these changes did notoccur in KO6w treated with Xe at the 6-weeks time point. These dataindicate an improvement in myocardial ischemia in response to Xeexposure and suggest that Xe-treated hearts have no hypertrophic changesand less myocardial ischemia. These changes also suggest a protectiverole of xenon-rich solution in heart diseases (FIG. 4B and suggest thatXe activity improves cardiac function and protects from myocardialischemia.

Increased Expression of BDNF in Heart and Brain Pretreated with Xe.

Xe preconditioning has the roles of neuroprotection in stroke (Peng etal, CNS Neurosci Ther; 2013 October; 19(10):773-84) and in brain damagefrom neonatal asphyxia (Ma et al, Journal of Cerebral Blood Flow &Metabolism (2006),199-208) in rats via the regulation of genes andsynthesis of BDNF. Previous studies have shown that BDNF is expressed inheart and may be involved in the molecular mechanisms of heart disease(Okada et al., 2012). To assess the possible role of BDNF in Xe activityon the cardiovascular system, relative BDNF expression levels in heartand brain were measured by ELISA in the presence of absence of XEtreatment (FIG. 5). As shown in FIG. 5A, relative BDNF levels wereincreased in KO6w/control/vehicle, as compared to WT6w. Furtherincreased BDNF levels were observed in KO6w vehicle versus KO6w. Inresponse to Xe exposure BDNF levels were further increased in the heart(KO6w Xe). Similar results were also observed in brain (FIG. 5B). Thesedata indicate that in the heart and brain, BDNF may be involved inXe-mediated changes (Pagel et al., 2010).

Levels of β-Amyloid in Plasma and Brain Pretreated with Xenon-RichSolution.

It has previously been reported that Xe may be involved in lipidhomeostasis, however the exact role and effects of Xe on suchhomeostasis was unclear (Golden et al., 2010; Jung et al., 2011).β-amyloid is a main component of brain deposits associated withAlzheimer's disease and also is related to lipid homeostasis (Shankar etal., 2008; Selkoe et al., 2001). To investigate whether Xe activitycould regulate β-amyloid levels Apo E-KO mice fed with high fat dietswere examined. In particular, β-amyloid levels in the plasma and brainsof treated and untreated animals were examined by ELISA (FIG. 6). Asshown in FIG. 6A, relative plasma β-amyloid levels were significantlyincreased in KO6w animals treated with the vehicle (and increase,although not significantly in KO6w) as compared to WT6w animals. Thisincrease was markedly attenuated in KO6w mice given Xe-rich solution.Similar results were also observed in brain tissue (FIG. 6B).Importantly, these data demonstrate that administration of a Xenon-richsolution has the potential for treatment of cerebral deposition disease.Accordingly, such solution may be used to attenuate the effects or delaythe progression of amyloid disease, such as Alzheimer's disease.

Xenon-Rich Solution to Increase Brain Tolerance to Ischemic Injury.

For these studies rats were divided into two groups, one group was givengastric delivery with water and another group was given gastric deliverywith xenon-rich-solution. After two weeks, the rats underwent middlecerebral occlusion for 2 hours. Infarct volumes were evaluated at 24hours after the brain injury. Rats given the xenon-rich solutiondeveloped smaller infarct size than controls (FIGS. 7A and 7B).Likewise, behavioral assessments including limb placement (FIG. 7C) andgrid walking (FIG. 7D), which are indicative of neurological functionwere completed. The group pre-treated with an oral Xe-rich solutionshowed better ability to perform the behavioral tasks. These dataindicate that administration of a xenon-rich-solution increases thebrain tolerance to ischemic insults and can result in significantabatement of neurological effects even following significant ischemicinjury.

Summary.

Studies presented here demonstrate the beneficial effects of oral Xedelivery for the neurological and cardiovascular systems. In particular,it has been shown that Xe intake was protective in a model system ofcardiovascular disease, where an wide range of disease markers could beimproved by Xe treatment. Likewise, it has been shown that oral Xe isneuroprotective. Not only was the orally delivered Xe able tosignificantly protect from ischemic injury, but Xe was also shown toreduce beta-amyloid load in treated animals, indicating that it may beuseful in treatment or prevention of degenerative neurological disease.Importantly, the data also show that even in an oral delivery system(e.g., such a lipid system described herein) can deliver a sufficientamount of Xe to provide measurable benefit treated animals.

TABLE 1 Echocardiographic Measurements LVID; d IVS; s LVID; s LVPW; s LVVol; s Heart Rate (mm) (mm) (mm) (mm) (μL) (BPM) WT 4.14 ± 0.18 1.26 ±0.09 2.86 ± 0.12 1.11 ± 0.08 30.55 ± 5.34 360 ± 11 wild type mice fedwith regular diet at baseline KO  3.6 ± 0.11* 1.28 ± 0.07 2.65 ± 0.111.13 ± 0.04 27.99 ± 3.46 439 ± 9* Apo E-KO mice fed with regular diet atbaseline WT6w 4.01 ± 0.05 1.18 ± 0.07 2.66 ± 0.08 1.18 ± 0.07 29.67 ±3.38 377 ± 15 WT mice fed with regular diet for 6 weeks KO6w  3.4 ±0.22* 1.32 ± 0.10 2.42 ± 0.13  1.2 ± 0.07 26.85 ± 2.83 428 ± 19* KO micefed with regular diet for 6 weeks KO6w  3.4 ± 0.16* 1.34 ± 0.11 2.47 ±0.09 1.41 ± 0.05 25.45 ± 4.19 459 ± 15* control KO mice fed with highfat diet and administered by PBS gavage for 6 weeks KO6w  3.4 ± 0.14*1.36 ± 0.06 2.57 ± 0.10  1.3 ± 0.05 26.26 ± 3.71 457 ± 14 vehicle KO fedwith high fat diet and vehicles for 6th week KO6w Xenon  4.0 ± 0.07^(§§)1.29 ± 0.05 2.65 ± 0.10 1.26 ± 0.07 26.01 ± 3.82 402 ± 13^(§) KO fedwith high fat diet and administered with Xenon- rich-solution for 6thweek *p < 0.05, **p < 0.01, KO/K06w compared to WT/WT6w, respectively; #p < 0.05, KO control/vehicle compared to KO 6w; ^(§)p < 0.05, ^(§§)p <0.01, ^(§§§) p < 0.001, KO xenon compared to KO vehicle. Vehicle iscaged molecular water with cyclodextrin without Xenon loaded.

Example 3 Material and Methods for Example 4 Preparation of CagedMolecular Enclosed Xenon

Xenon was enclosed into a soluble caged molecules (e.g., cyclodextrin).To remove possible residue molecules from cage, the caged molecular wasbaked at 40-80° C. under vacuum for overnight. To enclose xenon intocaged molecules, xenon was incubated with caged molecular in a sealedvial under 2-10 atm pressure at 4 to −180° C. for overnight to 3 days.

Preparation of Pure Xenon Supersaturated Water

Pure water was degassed under 20-80 mbar vacuum at room temperature forovernight. Xenon (99.999% Medical grade, Matheson Tri-Gas®, Houston,Tex., USA) was re-dissolved into degased water by pressure water with2-10 atm xenon gas at 4° C. for overnight to 3 days.

Preparation of Xe-Rich-Water

Xe-rich-water is composed of Xe directly dissolved in water and cagingwith hydroxypropyl-beta-cyclodextrin (hp-beta-CD) in water. To prepare aXe-rich-water, Xenon supersaturated water (10 ml) was injected into thevial containing 5 mg caged molecular-xenon complexes (0.5 mg/ml). Theresulting mixture was incubated under 2-10 atm pressure at 4° C. forovernight to 3 days.

Measurement of Xe Dissolved in Xenon-Rich-Water

To measure the amount of Xe dissolved in a Xe-rich-water. The solutionwas warmed to room temperature and the pressure over Xe-rich-watersample was released. The solution was then warmed up to 80° C. in a vialwith a silicone-rubber seal (Thermo Scientific SepraSeal® (ThermoScientific, Hudson, N.H., USA) sealed top for 2 hours. After coolingdown to room temperature, a syringe with a 17 gauge needle was insertedinto a vial through the silicone-rubber seal. The released Xe gaspresent in the top spacer formed pressure, which pushed Xe gas into thesyringe. The amount of Xe released into syringe was then measured.

Animals

All animal studies were approved by the Animal Welfare Committee at TheUniversity of Texas Health Science Center at Houston. Wild type (WT) andApo E knockout (KO) transgenic mice were purchased from JacksonLaboratory (Bar Harbor, Me., USA). Wild type control mice used wereC57BL/6J to compare with the Apo E KO mice with the same geneticbackground. Eight- to eleven-month old male and female WT and KO micewere fed with a high fat diet (Harlan Laboratories, USA) andadministered with caged molecular water with CD, but without Xe(vehicle) or Xe-rich-water, which included caged molecular water with CDloaded with Xe (0.2 to 10 ml per day) for 6 weeks.

Echocardiographic Measurements and Electrocardiographic Images (In Vivo)

Baseline measurements by echocardiography were obtained before feedingwith the high fat diet. Cardiac morphology and function were assessed byserial M-mode echocardiography using a Vevo 770 Imaging System(VisualSonics Inc., Ontario, Canada) equipped with a 30 MHz microprobe.M-mode ventricular measurements were taken at 6-weeks after the feeding.Electrocardiographic (ECG) data was obtained. Echo data (HR, heart rate;LVID, left ventricular internal dimension; IVS, intra-ventricularseptum; LVPW, left ventricular posterior wall; FS, fractionalshortening; SV, stroke volume; EF, ejection fraction; CO, cardiacoutput; LV Vol, LV volume; LV mass corrected) were analyzed with theanalysis software (VisualSonics Inc., Ontario, Canada).

Blood Pressure Measurement

Mice blood pressure was monitored non-invasively utilizing a tail-cuffplaced on mice tail to occlude the blood flow.

Protein Assays

Fresh frozen heart and brain tissues were slightly thawed on crushed iceto allow dissection of the hearts and brains. Tissue samples werehomogenized by sonicating for 2-3 bursts of 20 seconds on ice using aminimal volume of radioimmunoprecipitation assay (RIPA) buffer (CellSignaling Technology, Inc. MA. USA)) containing protease inhibitors(complete protease inhibitor cocktail, Sigma) and centrifuged for 10 minat 4° C. at 14,000×g. The supernatant was removed. The proteinconcentration was determined by using a Bradford Protein Assay (Bio-Rad,CA, USA)

β-Amyloid Measurements

β-amyloid peptide (Aβ1-40) content in both brain and blood weredetermined using a Mouse/Rat Amyloid β (1-40) High Specific ELISA AssayKit (IBLAmerican, Minneapolis, Minn., USA). Following instructions, thesamples were added in the pre-coated 96-well microtiter plates forincubation overnight at 4° C. After washing, the antibodies were addedand incubated. Absorbance was measured by using SpectroMax Microplatereader (Bio-Tek Instruments) at 450 nm. All samples were analyzed induplicate.

Western Blot Analysis Cardiac Troponin Expression in Heart Tissue

Western blot analysis was carried out as previously described (Yin, X,Molecular Pharmacology) using cardiac troponin I (cTnI) (Cell SignalingTechnology, Inc., Danvers, Mass., USA). For immunoblot analyses, sampleswere resolved by SDS-PAGE (4-12%) gradient gels, and transferred toPolyvinilidene Fluoride (PVDF) membranes. Blots were then incubatedovernight at 4° C. with primary antibodies and washed three times withTBS containing 0.1% Tween 20 (TBST), and then probed with secondaryantibodies (LI-COR Biosciences, Lincoln, Nebr., USA) following themanufacturer's instructions. Densitometric analyses of the immunoblotswere performed with an Odyssey Infared Imager (LI-COR Biosciences).

Statistical Analysis

Data were processed using Microsoft Excel and GraphPad Prism 5.0. Allvalues are expressed as the mean±S.E.M. Comparisons between two groupswere determined using unpaired 2-tailed Student's t test. Analysis wasperformed using one-way ANOVA, followed by a Tukey's post hoc multiplecomparison test when multiple groups were compared. P values of lessthan 0.05 were considered significant.

Example 4 Results of Further Studies with Xe Enhanced Water XenonDissolved in Xe-Rich-Water

Cyclodextrin (CD) is a multifunctional caged molecule employed the infood, pharmaceutical, and chemical industries. Cyclodextrins provide ahydrophobic interior and a hydrophilic exterior. Studies described herewere undertaken to determine if these properties could be used, toincrease the solubility of Noble gases, such as xenon.

Data from initial studies demonstrated that the inclusion of Xenon intocyclodextrin (hp-beta-CD) is highly related to pressure (FIG. 10C) andtemperature (FIG. 10D). Increased pressure resulted in increased amountsof Xe encapsulation as shown in FIG. 10C. Likewise, encapsulation ofgaseous Xe at low temperature was more efficient (FIG. 10D). Forexample, the studies showed that, at 3 atm, −80° C., a total of 5 ml ofxenon could be encapsulated in a hp-beta-CD cage (0.5 mg/ml ofhp-beta-CD was used).

Xenon solubility in water is, likewise, highly related to the pressureand temperature of the solution. By incubation of degassed water withpure xenon gas at 4° C., 3 atm for 4 hours to overnight, a total 6.5 mlxenon gas was dissolved into 5 ml water. To make Xe-rich-water,Xe-saturated water was incubated with Xe-CD under 3 atm pressure at 4°C. A pressure of 3 atm was used here since, typically, a standardbeverage container can withstand 80-90 psi (5.4-6.1 atm) pressure (i.e.,a typical can of a soft drink such as Coca-Cola™ classic products havean internal pressure of 55 psi (3.7 atm) at 75° F.). As showed in FIG.11, in the presence of water as a media, 19 ml Xenon gas was includedinto caged molecules and dissolved in water (with a starting volume of 5ml of water). Thus, the formulation achieved a total Xe content of 22.4mg Xe per ml of the CD-water solution (at CD concentration of 0.5 mg/mlhp-beta-CD).

Xenon-Rich-Water Increases the Tolerance of Heart to Ischemic Stress

To examine the effect of Xe activity on prevention of heart disease micewere divided into 4 groups, (1) wild type fed with normal food and watercontrol (WT); (2) Apo E knockout mice fed with high fat diet and normalwater control; (3) Apo E knockout mice fed with high fat diet andvehicle control (feed with water containing cyclodextrin but no xenon),and (4) Apo E knockout mice fed with high fat diet and Xe-rich-water(Xenon loaded into cyclodextrin, i.e. molecular caged xenon).Echocardiography was used to assess cardiac dimensions and function atbaseline, and at 6-weeks after feeding.

Intra-ventricular septum (IVS), left ventricular posterior wallthickness (LVPW), left ventricular (LV) volume, and LV internaldimensions (ID) were measured at diastole and systole byechocardiography at baseline and following 6-weeks of treatment (FIG.12). High fat diet caused the ventricular wall thickness to besignificantly increased, as is typical for ApoE KO animals. However,this pathological change did not occur in ApoE KO mice receiving 6-weeksof Xe-rich-water treatment, as compared to mice which received onlywater with cyclodextrin (FIG. 12). Heart rate (HR) also increased inApoE KO mice fed a high fat diet and treated with vehicle. Again,treatment with Xe-rich-water prevented this increase. These resultssuggest, as indicated in the studies above, that oral Xe-rich-waterconsumption suppresses progression of cardiac hypertrophy. Furthermore,levels of Xe in the encapsulated water formulations were high enough toachieve beneficial effect.

Cardiac function was also assessed at baseline and 6-weeks ofadministration of Xe-rich-water (FIG. 12). At baseline and 6-weeks, LVfractional shortening (FS), (EF), and cardiac output (CO) were decreasedin ApoE KO mice fed with a high fat diet, as compared to WT and WT6wtreated mice. In ApoE KO mice that received administration ofXe-rich-water (KO6w Xe) hearts from the mice significantly protectedfrom these decreases as compared to KO6w vehicle at the 6-week timepoint, (FIG. 12A-C; respectively).

ECG data show changes in T wave, ST segment, and QRS complex inKO/KO6w/control/vehicle hearts compared to WT/WT6w respectively,compatible with myocardial ischemia. These changes did not occur in thehearts of ApoE KO mice that received administration of Xe-rich-water(KO6wXe hearts) 6-weeks. This indicates that administration ofXe-rich-water reduces myocardial ischemia.

Troponin and CKMB (Creatine Kinase) are two markers of heart ischemia.Further studies measured the plasma CKMB level and troponin expressionin heart tissue. These studies showed that the level of the two markerswere increased in controls and was decreased in ApoE KO mice thatreceived administration of Xe-rich-water (FIG. 13). These data furtherconfirmed that the consumption of Xe-rich water increased the toleranceof the heart to ischemic stress.

Xenon-Rich-Water Stabilize Blood Pressure

Further analysis of Xe-treated mice indicated that oral administrationof the Xe-rich drinking water on a daily basis for 6 weeks significantlydecreases both systolic and diastolic blood pressure (Table 2), whileincreasing the heart contractility.

TABLE 2 Xe-rich-water stabilize blood pressure ApoE ApoE ApoE Baseline6W-control 6W-vehicle 6W-Xenon (n = 19) (n = 3) (n = 5) (n = 5) SystolicBP 98 ± 7 122 ± 4* 121 ± 5* 103 ± 3^(§) (mmHg) Diastolic BP 74 ± 5  94 ±3*  91 ± 2*  77 ± 3^(§) (mmHg) *p < 0.05, KO/KO6W compared to Apo E fedwithout high fat diet (baseline); ^(§)p < 0.05, KO Xenon compared to KOvehicle

Xenon-Rich-Water Reduces Beta-Amyloid in Both Brain Tissue and Blood

Studies were also undertaken to determine the effects of Xe-wateradministration on β-amyloid in brain and blood (see FIG. 14). For thesestudies the well characterized ApoE-KO mouse model system forAlzheimer's disease was used. These mice exhibit increased levels ofserum and brain β-amyloid levels as compared to control mice. However,administration of Xe-water to the mice over a period of six weeksresulted in decreased levels of both serum and brain β-amyloid(achieving levels similar to control animals).

All of the methods disclosed and claimed herein can be made and executedwithout undue experimentation in light of the present disclosure. Whilethe compositions and methods of this invention have been described interms of preferred embodiments, it will be apparent to those of skill inthe art that variations may be applied to the methods and in the stepsor in the sequence of steps of the method described herein withoutdeparting from the concept, spirit and scope of the invention. Morespecifically, it will be apparent that certain agents which are bothchemically and physiologically related may be substituted for the agentsdescribed herein while the same or similar results would be achieved.All such similar substitutes and modifications apparent to those skilledin the art are deemed to be within the spirit, scope and concept of theinvention as defined by the appended claims.

REFERENCES

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

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What is claimed is:
 1. A nutraceutical composition comprising: (i) asubstantially aqueous component comprising a dissolved Noble gas, aportion of the Noble gas being encapsulated with a water-solublepolymer; and/or (ii) an edible oil component comprising a dissolvedNoble gas.
 2. The composition of claim 1, wherein the Noble gas isHelium, Neon, Argon, Krypton or Xenon.
 3. The composition of claim 1,wherein the Noble gas is Xenon.
 4. The composition of claim 1, whereinthe composition comprises a mixture of two or more Noble gases.
 5. Thecomposition of claim 1, wherein the composition comprises an emulsion.6. The composition of claim 1, wherein water-soluble polymer iscyclodextrin.
 7. The composition of claim 6, wherein the cyclodextrin isgamma- or beta-cyclodextrin.
 8. The composition of claim 6, wherein thecyclodextrin is beta-cyclodextrin.
 9. The composition of claim 6,wherein the composition comprises about 0.1 to about 1.0 mg/ml of acyclodextrin molecule.
 10. The composition of claim 1, wherein the oilcomprises polyunsaturated fatty acids (PUFA).
 11. The composition ofclaim 1, wherein the oil comprises at least 1%, 5%, 10%, 20%, 30%, 40%,50%, 60%, 70%, 80% or 90% PUFAs.
 12. The composition of claim 1, whereinthe oil component is saturated with xenon or argon gas.
 13. Thecomposition of claim 1, wherein the edible oil component comprisessoluble xenon gas.
 14. The composition of claim 1, wherein the edibleoil is essentially free of oxygen.
 15. The composition of claim 1,wherein the oil comprises canola oil, flaxseed oil, rapeseed oil,soybean oil, walnut oil, fish oil, safflower oil, chia seed oil,sunflower seed oil, sesame seed oil, seaweed oil, corn oil, cotton seedoil, peanut oil, palm oil, avocado oil, coconut oil, or olive oil. 16.The composition of claim 1, wherein the oil comprises omega-3 fattyacids.
 17. The composition of claim 1, further defined as an emulsioncomprising: (a) 25% to 50% by volume oil, said oil being saturated witha Noble gas; and (b) 30% to 75% by volume aqueous solution.
 18. Thecomposition of claim 1, further defined as an emulsion comprising: (a)15% to 75% by volume oil, said oil being saturated with a Noble gas; and(b) 25% to 85% by volume aqueous solution.
 19. The composition of claim1, wherein the aqueous solution comprises water, fruit juice, vegetablejuice or an alcohol.
 20. The composition of claim 1, further comprisingphospholipid, detergent, or protein components.
 21. The composition ofclaim 20, wherein the detergent is a plant surfactant, a syntheticdetergent or a bile acid.
 22. The composition of claim 20, wherein thedetergent is lithocholic acid, deoxycholic acid, taurocholic acid,glycocholic acid, chenodeoxycholic acid, or cholic acid.
 23. Thecomposition of claim 20, wherein the phospholipid is egg phosphocholine(egg PC), soybean PC, DPPC or DOPC.
 24. The composition of claim 20,wherein the protein is milk protein, whey protein, soy protein isolate,or bovine serum albumin.
 25. The composition of claim 1, furthercomprising between about 1 and 50 g of xenon per ml of oil.
 26. Thecomposition of claim 1, comprising: (a) 15% to 75% by volume olive oil,said oil being saturated with xenon or argon gas; (b) 25% to 85% byvolume aqueous solution; and one or more of a phospholipid, a detergentor a protein.
 27. The composition of claim 1, comprising: (a) 25% to 50%by volume olive oil, said oil being saturated with xenon or argon gas;(b) 50% to 75% by volume aqueous solution; (c) 10-30 mg/mlphosphocholine; (d) 10-50 mg/ml BSA; and (e) 1-5 mg/ml lithocholic acid.28. The composition of claim 1, comprising: (a) 15% to 75% by volumeolive oil, said oil being saturated with xenon or argon gas; (b) 25% to85% by volume aqueous solution; (c) 10-30 mg/ml phosphocholine; (d)10-50 mg/ml BSA; and (e) 1-5 mg/ml lithocholic acid.
 29. The compositionof claim 1, further defined as a herbal, vitamin or energy-providingnutraceutical beverage.
 30. The composition of claim 1, furthercomprising a preservative, flavoring agent, dye, vitamin, anti-oxidant,or plant extract.
 31. The composition of any one of claims 1-30, saidcomposition comprised in a gas impermeable container.
 32. Thecomposition of claim 31, wherein the container comprises about 1 ml to 2liters of the composition.
 33. The composition of claim 32, wherein thecontainer comprises about 1 mg to 20 g, 1 mg to 10 g, 1 mg to 1 g, 1 to100 mg, 1 to 50 mg, 1 to 25 mg or 1 to 10 mg of Xe.
 34. The compositionof claim 31, wherein the container comprises a one-way value to releasethe composition for oral consumption without exposing the entire contentto the atmosphere.
 35. The composition of claim 32, wherein thecontainer is pressurized.
 36. The composition of claim 35, wherein thecontainer is pressurized with a Noble gas.
 37. The composition of claim35, further comprising CO₂.
 38. A single serving nutraceuticalcomprising a composition of any one of claims 1-30, in a gas impermeablecontainer.
 39. The single serving beverage of claim 38, wherein thecontainer is a bottle.
 40. The single serving beverage of claim 39,wherein the container has 1 ml to 1.0 1 ml of the composition.
 41. Thesingle serving beverage of claim 38, wherein the Noble gas comprises Xe.42. The single serving beverage of claim 41, having about 1 mg to 20 g,1 mg to 10 g, 1 mg to 1 g, 1 to 100 mg, 1 to 50 mg, 1 to 25 mg or 1 to10 mg of Xe.
 43. A single serving nutraceutical composition comprisingabout 25 to 500 ml of a substantially aqueous component and about 0.1 mgto 20 g of dissolved Noble gas, wherein a portion of the Noble gas inencapsulated to enhance aqueous solubility.
 44. A method of improvingthe health or well-being of a subject comprising providing a liquid orsemi-liquid composition formulated for oral consumption, comprising adissolved Noble gas.
 45. The method of claim 44, wherein the liquidcomposition is saturated or supersaturated with a Noble gas.
 46. Themethod of claim 45, wherein the Noble gas comprises Xe.
 47. The methodof claim 44, wherein the liquid composition is a composition inaccordance with any one of claims 1-42.
 48. A method of providingneurological or cardiovascular protection is a subject comprising orallyadministering an effective amount of a composition comprising dissolvedNoble gas.
 49. The method of claim 48, wherein the subject has or isrisk for atherosclerosis, Alzheimer's disease, thrombotic stroke,hemorrhage stroke, heart failure or cardiac hypertrophy.
 50. The methodof claim 48, wherein the subject is a human.
 51. The method of claim 50,wherein the Noble gas comprises Xe.
 52. The method of claim 51,comprising administering about 0.1 mg to 20 g/day of Xe to the subject.53. The method of claim 52, comprising administering about 500 mg to 10g, 500 mg to 5 g, 500 mg to 2 g, 1 to 100 mg, 1 to 50 mg, 1 to 25 mg or1 to 10 mg per day of Xe to the subject.
 54. The method of claim 48,wherein the composition is administered weekly, daily, twice a day,three times a day, every six hours, every three hours or hourly.
 55. Themethod of claim 54, wherein the composition is administered over theperiod of a week, two weeks, a month or a year.
 56. The method of claim48, further defined as a method for treating or preventing aneurological disease or neurological injury.
 57. The method claim 56,wherein the neurological disease is Alzheimer's disease.
 58. The methodof claim 57, further defined as a method reducing beta-amyloid levels inthe subject.
 59. The method of claim 57, further defined as a method fortreating or preventing the progression of Alzheimer's disease is asubject.
 60. The method of claim 57, wherein the subject is at risk fordeveloping Alzheimer's disease.
 61. The method of claim 57, wherein thesubject has or is diagnosed with a genetic predisposition forAlzheimer's disease.
 62. The method of claim 56, wherein theneurological injury is thrombotic or ischemic stroke.
 63. A method forreducing a marker of inflammation in a subject comprising orallyadministering an effective amount of a composition dissolved Noble gas.64. The method of any one of claims 48-63, wherein the compositioncomprises Noble gas that has been encapsulated to enhance aqueoussolubility.
 65. The method of any one of claims 48-63, wherein thecomposition comprises: (i) a substantially aqueous component comprisinga dissolved Noble gas, a portion of the Noble gas being encapsulatedwith a water-soluble polymer; and/or (ii) an oil component comprising adissolved Noble gas.
 66. The method of claim 65, wherein the Noble gasis Helium, Neon, Argon, Krypton or Xenon.
 67. The method of claim 65,wherein the Noble gas is Xenon.
 68. The method of claim 65, wherein thecomposition comprises a mixture of two or more Noble gases.
 69. Themethod of claim 65, wherein the composition comprises an emulsion. 70.The method of claim 65, wherein water-soluble polymer is cyclodextrin.71. The method of claim 70, wherein the cyclodextrin is gamma- orbeta-cyclodextrin.
 72. The method of claim 70, wherein the cyclodextrinis beta-cyclodextrin.
 73. The method of claim 70, wherein thecomposition comprises about 0.1 to about 1.0 mg/ml of a cyclodextrin.74. The method of claim 65, wherein the oil comprises polyunsaturatedfatty acids (PUFA).
 75. The method of claim 65, wherein the oilcomprises at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or90% PUFAs.
 76. The method of claim 65, wherein the oil component issaturated with xenon or argon gas.
 77. The method of claim 65, whereinthe edible oil component comprises soluble xenon gas.
 78. The method ofclaim 65, wherein the edible oil is essentially free of oxygen.
 79. Themethod of claim 65, wherein the oil comprises canola oil, flaxseed oil,rapeseed oil, soybean oil, walnut oil, fish oil, safflower oil, chiaseed oil, sunflower seed oil, sesame seed oil, seaweed oil, corn oil,cotton seed oil, peanut oil, palm oil, avocado oil, coconut oil, orolive oil.
 80. The method of claim 65, wherein the oil comprises omega-3fatty acids, omega-6 fatty acids or omega-9 fatty acids.
 81. The methodof claim 65, further defined as an emulsion comprising: (a) 25% to 50%by volume oil, said oil being saturated with a Noble gas; and (b) 30% to75% by volume aqueous solution.
 82. The method of claim 65, furtherdefined as an emulsion comprising: (a) 15% to 75% by volume oil, saidoil being saturated with a Noble gas; and (b) 25% to 85% by volumeaqueous solution.
 83. The method of claim 65, wherein the aqueoussolution comprises spring water, fruit juice or vegetable juice.
 84. Themethod of claim 65, further comprising phospholipid, detergent, orprotein components.
 85. The method of claim 84, wherein the detergent isa plant surfactant, a synthetic detergent or a bile acid.
 86. The methodof claim 84, wherein the detergent is lithocholic acid, deoxycholicacid, taurocholic acid, glycocholic acid, chenodeoxycholic acid, orcholic acid.
 87. The method of claim 84, wherein the phospholipid is eggphosphocholine (egg PC), soybean PC, DPPC or DOPC.
 88. The method ofclaim 84, wherein the protein is milk protein, whey protein, soy proteinisolate, or bovine serum albumin.
 89. The method of claim 65, furthercomprising between about 1 and 50 mg of xenon per ml of oil.
 90. Themethod of claim 65, wherein the composition comprises: (a) 15% to 75% byvolume olive oil, said oil being saturated with xenon or argon gas; (b)25% to 85% by volume aqueous solution; and one or more of aphospholipid, a detergent or a protein.
 91. The method of claim 65,wherein the composition comprises: (a) 25% to 50% by volume olive oil,said oil being saturated with xenon or argon gas; (b) 50% to 75% byvolume aqueous solution; (c) 10-30 mg/ml phosphocholine; (d) 10-50 mg/mlBSA; and (e) 1-5 mg/ml lithocholic acid.
 92. The method of claim 65,wherein the composition comprises: (a) 15% to 75% by volume olive oil,said oil being saturated with xenon or argon gas; (b) 25% to 85% byvolume aqueous solution; (c) 10-30 mg/ml phosphocholine; (d) 10-50 mg/mlBSA; and (e) 1-5 mg/ml lithocholic acid.
 93. A method of making anaqueous composition comprising a Noble gas comprising: (a) incubating aNoble gas with a water soluble encapsulating polymer; and (b) exposingthe encapsulated Noble gas to an aqueous to produce an aqueouscomposition comprising the Noble gas. at a pressure of between about 2atm and 10 atm, at a temperature of between about 4° C. and −180° C. forat least 4 hours to produce an encapsulated Noble gas solution at apressure of between about 2 atm and 10 atm, at a temperature of betweenabout 20° C. and 1° C. for at least 4 hours
 94. The method of claim 93,wherein the incubating of step (a) is performed at a pressure of betweenabout 2 atm and 8 atm, 2 atm and 5 atm, 2 atm and 4 atm or at a pressureof about 3 atm.
 95. The method of claim 93, wherein the incubating ofstep (a) is performed at a temperature of between about 0° C. and −150°C., −20° C. and −150° C., −20° C. and −100° C., −40° C. and −100° C. orat a temperature of about −80° C.
 96. The method of claim 93, whereinthe incubating of step (a) is for a period of at least 8 hours, 12hours, 24 hours, 48 hours or for between 8 hours and three days.
 97. Themethod of claim 93, wherein the exposing of step (b) is performed at apressure of between about 2 atm and 8 atm, 2 atm and 5 atm, 2 atm and 4atm or at a pressure of about 3 atm.
 98. The method of claim 93, whereinthe exposing of step (b) is performed at a temperature of between about15° C. and 1° C., 10° C. and 1° C., 8° C. and 2° C., 6° C. and 2° C. orat a temperature of about 4° C.
 99. The method of claim 93, wherein theexposing of step (b) is for a period of at least 8 hours, 12 hours, 24hours, 48 hours or for between 8 hours and three days.
 100. The methodof claim 93, wherein the aqueous solution comprises a dissolved Noblegas.
 101. The method of claim 99, wherein the aqueous solution issaturated with a Noble gas.
 102. The method of claim 100, wherein theaqueous solution is saturated with a Noble gas by a method comprising:(i) obtaining a degassed aqueous solution; and (ii) exposing thedegassed aqueous solution to a Noble gas at a pressure of between about2 atm and 10 atm, at a temperature of between about 20° C. and 1° C. forat least 4 hours to produce an aqueous solution saturated with the Noblegas.
 103. The method of claim 93, wherein the Noble gas is argon orxenon.
 104. The method of claim 103, wherein the Noble gas is xenon.105. The method of claim 93, wherein the Noble gas comprises a mixtureof two or more Noble gases.
 106. The method of claim 93, whereinwater-soluble encapsulating polymer is cyclodextrin.
 107. The method ofclaim 106, wherein the cyclodextrin is gamma- or beta-cyclodextrin. 108.The method of claim 106, wherein the cyclodextrin is beta-cyclodextrin.109. The method of claim 108, wherein the beta-cyclodextrin ishydroxypropyl-beta-cyclodextrin.
 110. The method of claim 93, furtherdefined as a method for making a pharmaceutical or nutraceuticalcomposition.
 111. The method of claim 93, wherein the aqueous solutioncomprises a preservative, flavoring agent, dye, vitamin, anti-oxidant,or plant extract.
 112. The method of claim 93, further comprising thestep of (c) packaging the aqueous composition comprising the Noble gasin a gas impermeable container.
 113. The method of claim 112, whereinthe container is pressurized.
 114. The method of claim 113, wherein thecontainer is pressurized with a Noble gas.
 115. The method of claim 112,wherein the container is a pill, a capsule, a foild or polymer packet ora bottle.
 116. An aqueous composition comprising a Noble gas produced bya method according to any one of claims 93-115.
 117. A method of makinga composition for oral administration of a Noble gas comprising: (a)solubilizing a Noble gas in an edible oil by mixing the oil and gas at apressure of between about 2 atm and 6 atm, at a temperature of betweenabout 0° C. and 25° C. to produce an edible oil comprising soluble Noblegas.